CN112500324B - Method for preparing thioamide compound - Google Patents

Abstract

The invention discloses a method for preparing thioamide compounds: under the protection of inert gas, carboxylate is used as substrate, sublimated sulfur is used as sulfur source, base is used as catalyst, formamide is used as solvent and amine source. At the reaction temperature of ℃, the reaction is stirred for 4 to 8 hours; the reaction result is subjected to post-treatment to obtain a thioamide compound. The invention is to synthesize thioamide compounds through a three-component one-pot method of carboxylate, sublimed sulfur and formamide; the method has the advantages of mild and safe operating conditions, short reaction time, simple process, simple operation and no need to use special instruments , The technical advantage of high product yield.

Description

Method for preparing thioamide compounds

technical field

The invention relates to a method for synthesizing a class of organic compounds, in particular to the synthesis of a class of pharmaceutical intermediates containing thioamide structural units, and belongs to the field of organic synthesis.

Background technique

As an important structural unit in C=S double bond compounds, the thioamide structure is widely present in drug molecules and has strong pharmaceutical activity; at the same time, it is also used to construct various sulfur-containing heterocycles (such as ketone, etc.) one of the most important precursors (Org. Lett. 2016, 18, 356.).

The earliest method of synthesizing thioamides is the sulfide of carbonamide by amide and Lawesson reagent or phosphorus pentasulfide (Chem. Commun. 2009, 46, 7122.); this method has the following disadvantages: the use of Lawesson's reagent or sulfur phosphorus The reagents are unstable, the price is relatively expensive, the atom economy is low, the odor is large, and it is not friendly to the environment.

In recent years, the use of Willgerodt-Kindler reaction to prepare thioamides has gradually emerged. This method uses aryl aldehydes, aryl/alkyl ketones, arylacetylenes, benzylamines, arylacetic acids, etc. as substrates to synthesize thioamides. amides (Org. Lett. 2009, 11, 3064.). Although this method improves the atomic utilization rate and step economy of the reaction, but the substrates are not widely applicable, the reaction conditions for some substrates are harsh, and the reaction temperature can reach up to 320 °C. limits its usefulness.

SUMMARY OF THE INVENTION

The problem to be solved by the present invention is to provide a method for preparing a thioamide compound by using carboxylate, sublimed sulfur and formamide as reaction raw materials with a simple and environmentally friendly process.

In order to solve the above-mentioned technical problems, the present invention provides a kind of method for preparing thioamide compounds:

1), under the protection of inert gas, with carboxylate as substrate, sublimation sulfur as sulfur source, alkali (cesium metal base) as catalyst, formamide as solvent and amine source, at 60～100 ℃ reaction temperature, stirring reaction 4 to 8 hours;

The molar ratio of carboxylate to sublimation sulfur is 1:1.5～2.0, and the molar ratio of carboxylate to base is 1:0.25～0.75;

2), post-processing the reaction product of step 1) to obtain a thioamide compound.

As the improvement of the method for preparing thioamide compounds of the present invention:

Carboxylic acid ester is

Formamide is

The -Ar is an aryl group, a substituted aryl group;

The -Alkyl is any of alkyl, cycloalkyl, alkylene oxide, substituted alkyl, and alkenyl;

The -R ₁ is any one of hydrogen, methyl and ethyl;

The -R ₂ and -R ₃ are any of hydrogen, methyl, ethyl, piperidinyl and morpholinyl.

As a further improvement of the method for preparing thioamide compounds of the present invention:

The cesium metal base is cesium carbonate, cesium hydroxide or cesium acetate.

As a further improvement of the method for preparing thioamide compounds of the present invention:

The ratio of the volume of the formamide to the weight of the carboxylate is 5 to 10 mL/g.

As a further improvement of the method for preparing thioamide compounds of the present invention:

The post-processing of described step 2) is:

After the reaction, water (deionized water) was added to the reaction result of step 1) to quench the reaction, followed by extraction with ethyl acetate (extracted with ethyl acetate three times), and the organic phase was washed with saturated brine (three times) , after drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating the filtrate (removing the solvent by rotary evaporation---ethyl acetate) to form a residue, and separating the residue by column chromatography on a silica gel column to collect the product containing the product (target product) The collected effluent was rotary evaporated (solvent was removed by rotary evaporator) to obtain the product (target product).

Note: When quenching the reaction solution, the volume ratio of water to formamide is 1:1; during each extraction, the volume ratio of ethyl acetate to formamide is 1:1, and the total amount of saturated brine is equal to ethyl acetate. total amount.

The reaction equation of the present invention is as follows:

details as follows:

Under the protection of inert gas (such as nitrogen), carboxylate, 1.5-2.0 molar equivalent of sublimated sulfur and 0.25-0.75 molar equivalent of base are sequentially added to formamide, and the reaction temperature is 60-100 ℃, stirring and reacting for 4-8 Hour. After the reaction is completed, add water (deionized water) equal to volume of formamide to the resulting reaction solution to quench the reaction solution, then extract three times with ethyl acetate of 3 times the volume of formamide, and use an equal volume of ethyl acetate to quench the reaction solution. The organic phase was washed three times with saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was removed from the solvent by a rotary evaporator to obtain the residue, and the residue was separated by column chromatography through a silica gel column, the effluent containing the target product was collected, and the combined effluent was rotated by a rotary evaporator to remove the solvent to obtain the target product.

The preparation method of the thioamide compound of the present invention has the following technical advantages:

1. The raw material carboxylate (such as benzyl formate) is cheap and easy to obtain, and the conversion rate is high, which can reduce the production cost; formamide is not only an amine source, but also acts as a solvent, which can effectively avoid the influence of solvent doping; Sulfur source can overcome the drawbacks of organic sulfur source and greatly improve the atom economy.

2. The use of cesium metal base as a catalyst can not only provide an alkaline environment, but also effectively catalyze the formation of thioamide compounds, reduce the reaction temperature, and save energy costs; at the same time, the one-pot method is used, no need to separate intermediate products. The target product can be directly obtained by stirring the reaction under normal pressure, which greatly simplifies the technological process, is simple in operation, has high safety, and is suitable for industrial production with low equipment investment.

3. The three wastes generated in the reaction process of the method of the present invention are less, which has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of thioamide compounds can be prepared by this method, so this method has a strong substrate generality. suitability.

4. The technical process is simple, high yield, less pollution, safe and environmentally friendly, green and mild.

To sum up, the present invention is to synthesize thioamide compounds through a three-component one-pot method of carboxylate, sublimated sulfur and formamide; the method has the advantages of mild and safe operating conditions, short reaction time, simple process and easy operation. , No need to use special equipment, high product yield advantages. The present invention is applicable to both aromatic and aliphatic.

Detailed ways

The following examples are intended to illustrate the present invention, but not to limit the scope of the present invention. The raw materials can be obtained from open commercial sources unless otherwise specified.

In the following case: the petroleum ether used in column chromatography separation is petroleum ether 60-90.

Embodiment 1, a kind of preparation method of thioamide compound, take benzyl formate as raw material:

Under nitrogen protection, benzyl formate (0.53 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 2.7 mL of formamide, and the reaction temperature was 80 °C. The reaction was stirred for 4 hours.

After the reaction, 2.7 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (2.7 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (2.7 mL) was used for extraction. ×3) Wash the organic phase and dry it with anhydrous sodium sulfate, filter (remove sodium sulfate), concentrate by rotary evaporation (remove ethyl acetate), purify by silica gel (100-200 mesh) column chromatography, use ethyl acetate/petroleum The mixed solution of ether (1:12 volume ratio) was used as the eluent, and the amount of the eluent was 300 ml. All the eluents were collected and concentrated by rotary evaporation; 0.38 g of a pale yellow solid was obtained, which was detected as N by NMR, N-dimethylthiobenzamide, yield 70.6%.

Embodiment 2, a kind of preparation method of thioamide compound, benzyl formate is raw material:

Under nitrogen protection, benzyl formate (0.53 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.44 g, 1.4 mmol) were added to 4.2 mL of N,N-dimethylformamide, The reaction was stirred for 8 hours at a reaction temperature of 60°C.

After the reaction, 4.2 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (4.2 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (4.2 mL ×3) Wash the organic phase, dry with anhydrous sodium sulfate, filter, concentrate by rotary evaporation, purify by silica gel (100-200 mesh) column chromatography, and use a mixed solution of ethyl acetate/petroleum ether (1:15 volume ratio) As eluent, the amount of eluent was 350ml, all the eluents were collected and concentrated by rotary evaporation; 0.55g of pale yellow solid was obtained, which was detected as N,N-dimethylthiobenzamide by NMR, Yield 85.8%.

Embodiment 3, a kind of preparation method of thioamide compound, take benzyl acetate as raw material:

Under nitrogen protection, benzyl acetate (0.59 g, 3.9 mmol), sublimed sulfur (0.20 g, 6.2 mmol), and cesium hydroxide (0.26 g, 1.8 mmol) were added to 4.1 mL of N-methylformamide, and the mixture was dissolved at 70 At the reaction temperature of °C, the reaction was stirred for 7 hours.

After the reaction was completed, 4.1 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (4.1 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (4.1 mL) was used for extraction. ×3) Wash the organic phase, dry with anhydrous sodium sulfate, filter, concentrate by rotary evaporation, purify by silica gel (100-200 mesh) column chromatography, and use a mixed solution of ethyl acetate/petroleum ether (1:15 volume ratio) As the eluent, the amount of the eluent was 350ml, and all the eluents were collected and concentrated by rotary evaporation; 0.41 g of a pale yellow solid was obtained, which was detected as N-methylthiobenzamide by NMR, and the yield was 70.3 %.

Embodiment 4, a kind of preparation method of thioamide compound, take benzyl acetate as raw material:

Under nitrogen protection, benzyl acetate (0.59 g, 3.9 mmol), sublimed sulfur (0.20 g, 6.2 mmol), and cesium hydroxide (0.44 g, 2.9 mmol) were added to 5.3 mL of N,N-diethylformamide , and the reaction was stirred for 6 hours at a reaction temperature of 80 °C.

After the reaction was completed, 5.3 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5.3 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5.3 mL) was used for extraction. ×3) Wash the organic phase, dry with anhydrous sodium sulfate, filter, concentrate by rotary evaporation, purify by silica gel (100-200 mesh) column chromatography, and use a mixed solution of ethyl acetate/petroleum ether (1:20 volume ratio) As the eluent, the amount of the eluent was 400ml, and all the eluents were collected and concentrated by rotary evaporation; 0.46 g of a brown solid was obtained, which was detected as N,N-diethylthiobenzamide by NMR, Yield 60.5%.

Embodiment 5, a kind of preparation method of thioamide compound, take benzyl propionate as raw material:

Under nitrogen protection, benzyl propionate (0.64 g, 3.9 mmol), sublimed sulfur (0.22 g, 7.0 mmol), and cesium acetate (0.48 g, 2.5 mmol) were added to 6.4 mL of N-formylmorpholine. At the reaction temperature of °C, the reaction was stirred for 4 hours.

After the reaction was completed, 6.4 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (6.4 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (6.4 mL) was used for extraction. ×3) Wash the organic phase, dry with anhydrous sodium sulfate, filter, concentrate by rotary evaporation, purify by silica gel (100-200 mesh) column chromatography, and use a mixed solution of ethyl acetate/petroleum ether (1:10 volume ratio) As the eluent, the amount of the eluent was 250ml, and all the eluents were collected and concentrated by rotary evaporation; 0.63 g of a bright yellow solid was obtained, which was detected as thiophenmorpholine by NMR, and the yield was 78.2%.

Embodiment 6, a kind of preparation method of thioamide compound, take benzyl propionate as raw material:

Under nitrogen protection, benzyl propionate (0.64 g, 3.9 mmol), sublimed sulfur (0.22 g, 7.0 mmol), and cesium acetate (0.48 g, 2.5 mmol) were added to 3.8 mL of N-formylpiperidine, and added to 90 At the reaction temperature of °C, the reaction was stirred for 5 hours.

After the reaction, 3.8 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (3.8 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (3.8 mL) was used for extraction. ×3) Wash the organic phase, dry with anhydrous sodium sulfate, filter, concentrate by rotary evaporation, purify by silica gel (100-200 mesh) column chromatography, and use a mixed solution of ethyl acetate/petroleum ether (1:10 volume ratio) As the eluent, the amount of the eluent was 250ml, and all the eluents were collected and concentrated by rotary evaporation; 0.60 g of brown solid was obtained, which was detected as N-thiobenzylpiperidine by NMR, and the yield was 75.3%. .

Embodiment 7, a kind of preparation method of thioamide compound, with formic acid-4-chlorobenzyl ester as raw material:

Under nitrogen protection, 4-chlorobenzyl formate (0.66 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylmethane In the amide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:15 volume ratio) The amount of the eluent was 350ml, and all the eluents were collected and concentrated by rotary evaporation; 0.66g of yellow solid was obtained, which was detected by NMR as 4-chloro-N,N-dimethylthiobenzamide, Yield 84.3%.

Embodiment 8, a kind of preparation method of thioamide compound, with formic acid-3-fluorobenzyl ester as raw material:

Under nitrogen protection, 3-fluorobenzyl formate (0.60 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylmethane In the amide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:15 volume ratio) The amount of the eluent was 350ml, and all the eluents were collected and concentrated by rotary evaporation; 0.47g of yellow solid was obtained, which was detected by NMR as 3-fluoro-N,N-dimethylthiobenzamide, Yield 65.6%.

Embodiment 9, a kind of preparation method of thioamide compound, with formic acid-4-methyl benzyl ester as raw material:

Under nitrogen protection, 4-methylbenzyl formate (0.59 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethyl In formamide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:15 volume ratio) The amount of the eluent was 350ml, and all the eluents were collected and concentrated by rotary evaporation; 0.55g of pale yellow solid was obtained, which was detected as 4-methyl-N,N-dimethylthiobenzyl by NMR. amide, yield 78.3%.

Embodiment 10, a kind of preparation method of thioamide compound, with formic acid-3-methoxybenzyl ester as raw material:

Under nitrogen protection, 3-methoxybenzyl formate (0.65 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylformaldehyde In the reaction temperature of 80 °C, the reaction was stirred for 8 hours.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:15 volume ratio) The amount of the eluent was 350ml, and all the eluents were collected and concentrated by rotary evaporation; 0.53g of bright yellow solid was obtained, which was detected by NMR as 3-methoxy-N,N-dimethylthiobenzene Formamide, yield 70.1%.

Embodiment 11, a kind of preparation method of thioamide compound, with formic acid-4-trifluoromethyl benzyl ester as raw material:

Under nitrogen protection, 4-trifluoromethylbenzyl formate (0.80 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-bismuth In methylformamide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:20 volume ratio) The amount of the eluent was 400ml, and all the eluents were collected and concentrated by rotary evaporation; 0.73g of yellow solid was obtained, which was detected by NMR as 4-trifluoromethyl-N,N-dimethylthiobenzene Formamide, yield 80.2%.

Embodiment 12, a kind of preparation method of thioamide compound, with formic acid-3-amino benzyl ester as raw material:

Under nitrogen protection, 3-aminobenzyl formate (0.59 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylmethane In the amide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:4 volume ratio) The amount of the eluent was 180ml, and all the eluents were collected and concentrated by rotary evaporation; 0.40g of yellow solid was obtained, which was detected as 3-amino-N,N-dimethylthiobenzamide by NMR, Yield 55.6%.

Embodiment 13, a kind of preparation method of thioamide compound, with formic acid-4-hydroxybenzyl ester as raw material:

Under nitrogen protection, 4-hydroxybenzyl formate (0.59 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylmethane In the amide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:4 volume ratio) The amount of the eluent was 190ml, and all the eluents were collected and concentrated by rotary evaporation; 0.57g of yellow solid was obtained, which was detected by NMR as 4-hydroxy-N,N-dimethylthiobenzamide, Yield 80.5%.

Embodiment 14, a kind of preparation method of thioamide compound, with formic acid-3-cyano benzyl ester as raw material:

Under nitrogen protection, 3-cyanobenzyl formate (0.63 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethyl In formamide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:3 volume ratio) The amount of the eluent was 150ml, and all the eluents were collected and concentrated by rotary evaporation; 0.33g of a brown solid was obtained, which was detected as 3-cyano-N,N-dimethylthiobenzyl by NMR. amide, yield 44.6%.

Embodiment 15, a kind of preparation method of thioamide compound, with formic acid-4-nitrobenzyl ester as raw material:

Under nitrogen protection, 4-nitrobenzyl formate (0.71 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethyl In formamide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:4 volume ratio) The amount of the eluent was 170ml, and all the eluents were collected and concentrated by rotary evaporation; 0.30g of brown solid was obtained, which was detected as 4-nitro-N,N-dimethylthiobenzyl by NMR. amide, yield 35.8%.

Embodiment 16, a kind of preparation method of thioamide compound, is formate-1-naphthyl ester raw material:

Under nitrogen protection, 1-naphthyl formate (0.73 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylformamide The reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:8 volume ratio) The amount of the eluent was 200ml, and all the eluents were collected and concentrated by rotary evaporation; 0.51g of dark yellow solid was obtained, which was detected by NMR as N,N-dimethyl-1-thionaphthalenecarboxamide, Yield 60.3%.

Embodiment 17, a kind of preparation method of thioamide compound, with formic acid-3-pyridine ester as raw material:

Under nitrogen protection, 3-pyridyl formate (0.53 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylformamide The reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:2 volume ratio) The amount of the eluent was 150ml, and all the eluents were collected and concentrated by rotary evaporation; 0.53g of yellow oil was obtained, which was detected as N,N-dimethyl-3-thiopyridinecarboxamide by NMR, Yield 80.2%.

Embodiment 18, a kind of preparation method of thioamide compound, takes formic acid-2-thiophene as raw material:

Under nitrogen protection, 2-thiophene formate (0.56 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylformamide The reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:7 volume ratio) The amount of the eluent was 200ml, and all the eluents were collected and concentrated by rotary evaporation; 0.43g of yellow solid was obtained, which was detected as N,N-dimethyl-2-thiothiophenecarboxamide by NMR. rate 65.5%.

Embodiment 19, a kind of preparation method of thioamide compound, with formic acid-3-furyl ester as raw material:

Under nitrogen protection, 3-furyl formate (0.50 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylformamide The reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:10 volume ratio) The amount of the eluent was 200ml, and all the eluents were collected and concentrated by rotary evaporation; 0.50g of brown oil was obtained, which was detected as N,N-dimethyl-3-thiofurancarboxamide by NMR. , the yield is 80.5%.

Embodiment 20, a kind of preparation method of thioamide compound, take n-butyl formate as raw material:

Under nitrogen protection, n-butyl formate (0.40 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 4 mL of N,N-dimethylformamide, At the reaction temperature of 80°C, the reaction was stirred for 8 hours.

After the reaction, 4 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (4 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (4 mL × 3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:15 volume ratio) The amount of the eluent was 300ml, and all the eluents were collected and concentrated by rotary evaporation; 0.43 g of a light yellow oil was obtained, which was detected as N,N-dimethyl-n-butane thioamide by NMR, and received rate 83.3%.

Embodiment 21, a kind of preparation method of thioamide compound, take isobutyl formate as raw material:

Under nitrogen protection, isobutyl formate (0.40 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 4 mL of N,N-dimethylformamide, At the reaction temperature of 80°C, the reaction was stirred for 8 hours.

After the reaction, 4 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (4 mL × 3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (4 mL × 3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:15 volume ratio) The amount of the eluent was 300ml, and all the eluents were collected and concentrated by rotary evaporation; 0.39g of light yellow oil was obtained, which was detected as N,N,2-trimethylpropane thioamide by NMR, and received rate 75.9%.

Embodiment 22, a kind of preparation method of thioamide compound, take cyclohexyl methyl acetate as raw material:

Under nitrogen protection, cyclohexyl methyl acetate (0.61 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylmethane In the amide, the reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:10 volume ratio) The amount of the eluent was 200ml, and all the eluents were collected and concentrated by rotary evaporation; 0.47g of yellow oil was obtained, which was detected as N,N-dimethylcyclohexanemethanethioamide by NMR, and the yield was 70.2%.

Embodiment 23, a kind of preparation method of thioamide compound, take tetrahydrofurfuryl alcohol acetate as raw material:

Under nitrogen protection, tetrahydrofurfuryl acetate (0.56g, 3.9mmol), sublimed sulfur (0.25g, 7.8mmol), cesium carbonate (0.32g, 1.0mmol) were added to 5mL of N,N-dimethylformamide The reaction was stirred for 8 hours at a reaction temperature of 80°C.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:10 volume ratio) The amount of the eluent was 250ml, and all the eluents were collected and concentrated by rotary evaporation; 0.41g of yellow oil was obtained, which was detected as N,N-dimethyloxolane-2-thiomethane by NMR. amide, yield 65.5%.

Embodiment 24, a kind of preparation method of thioamide compound, take cinnamyl acetate as raw material:

Under nitrogen protection, cinnyl acetate (0.69 g, 3.9 mmol), sublimed sulfur (0.25 g, 7.8 mmol), and cesium carbonate (0.32 g, 1.0 mmol) were added to 5 mL of N,N-dimethylformamide. At the reaction temperature of 80°C, the reaction was stirred for 8 hours.

After the reaction, 5 mL of deionized water was added to the obtained reaction solution to quench the reaction solution, followed by extraction with ethyl acetate (5 mL×3) to obtain an aqueous phase and an organic phase, respectively, and then saturated brine (5 mL×3) was used. The organic phase was washed, dried with anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, purified by silica gel (100-200 mesh) column chromatography, and eluted with a mixture of ethyl acetate/petroleum ether (1:10 volume ratio) The amount of the eluent was 260ml, and all the eluents were collected and concentrated by rotary evaporation; 0.51g of yellow solid was obtained, which was detected by NMR as (E)-N,N-dimethyl-3-phenylpropane -2-enesulfamide, yield 68.9%.

Comparative Example 1. The cesium carbonate used as the catalyst in Example 2 was changed as described in Table 1 below, the molar dosage remained unchanged, and the rest were identical to those of Example 2.

The final results obtained are described in Table 1 below.

Table 1

Finally, it should also be noted that the above enumeration is only a few specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many modifications are possible. All deformations that those of ordinary skill in the art can directly derive or associate from the disclosure of the present invention shall be considered as the protection scope of the present invention.

Claims (3)

1. A process for the preparation of thioamide compounds, characterized in that:

1) under the protection of inert gas, taking carboxylic ester as a substrate, sublimed sulfur as a sulfur source, alkali as a catalyst, formamide as a solvent and an amine source, and stirring to react for 4-8 hours at the reaction temperature of 60-100 ℃;

the molar ratio of the carboxylic ester to the sublimed sulfur is 1: 1.5-2.0, and the molar ratio of the carboxylic ester to the alkali is 1: 0.25-0.75;

carboxylic acid ester

，

The formamide is

，

Ar is aryl or substituted aryl;

the Alkyl is any one of Alkyl, cycloalkyl, epoxyalkyl, substituted Alkyl and alkenyl;

the R is₁Any one of hydrogen radical, methyl and ethyl;

the R is₂， R₃Any one of hydrogen radical, methyl, ethyl, piperidyl and morpholinyl;

the alkali is cesium carbonate, cesium hydroxide or cesium acetate;

2) carrying out post-treatment on the reaction product obtained in the step 1) to obtain a thioamide compound;

the thioamide compound is as follows:

。

2. the process for producing thioamide compounds as claimed in claim 1, wherein:

the ratio of the volume of formamide to the weight of carboxylate is 5-10 mL/g.

3. The process for producing thioamide compounds as claimed in claim 1 or 2, wherein:

the post-treatment of the step 2) comprises the following steps:

after the reaction is finished, adding water into the reaction product obtained in the step 1) for quenching reaction, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous sodium sulfate, filtering, concentrating a filtrate to form a residue, carrying out column chromatography separation on the residue by using a silica gel column, collecting an effluent containing a product, and carrying out rotary evaporation on the collected effluent to obtain the product.