A method for synthesizing beta-trifluoromethylthio amide by using silver trifluoromethylthiolate

Abstract

The application belongs to the technical field of medicine preparation, and particularly relates to a synthesis method of beta-trifluoromethylthio amide participated by silver trifluoromethylthiol, and the specific steps are as follows: in step 1, acrylamide, silver trifluoromethane thiol, acid and solvent are put into a thick-walled pressure-resistant tube for reaction, the reaction time is 8h, and the reaction temperature is 40-60 DEG C; in step 2, after the reaction is completed, dichloromethane is added to dilute the reaction solution, the organic solvent is removed by rotary evaporation, and the remaining product is separated by column chromatography to obtain beta-trifluoromethylthio saturated amide. By using the method in the application, the preparation of beta-trifluoromethylthio saturated amide can be realized in one step, the operation process is simple, the reaction efficiency is effectively improved, in addition, the reaction temperature is only 40-60 DEG C, and the method has the advantages of low reaction energy consumption, low overall production cost and high degree of technical environmental friendliness.

Description

A method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol. Background Technology

[0002] Aromatic amines are extremely important organic raw materials, widely used in the production of dyes, pharmaceuticals, agrochemicals, additives, surfactants, textile auxiliaries, chelating agents, polymers, and flame retardants. Aromatic amines are also important intermediates in organic synthesis, and with the rapid development of my country's industry and economy, the demand for aromatic amines from various related industries will continue to grow.

[0003] The trifluoromethylthio group is a common functional group characterized by high stability, high electronegativity, and strong lipophilicity. Introducing a trifluoromethylthio group into organic compounds can enhance the lipophilicity of the molecule to the cell membrane, thereby improving the absorption and delivery of active ingredients in drugs, and thus achieving therapeutic effects and regulating cellular metabolism. Numerous studies have shown that drugs containing trifluoromethylthio groups penetrate the body better than traditional fluorine-containing drugs and exhibit stronger selectivity for target organs. Therefore, trifluoromethylthio groups are widely used in multi-molecule drugs and bioactive molecular structures. However, current synthetic routes for drugs containing trifluoromethylthio groups are relatively complex, requiring special trifluoromethylthio reagents, high temperatures, and metal catalysis.

[0004] A Chinese invention patent with application number CN201610547078.4 discloses an indanone compound with a trifluoromethylthio group and its preparation method. The patent uses an acetylenone compound and a silver trifluoromethylthioalkyl alcohol compound as raw materials, a persulfate reagent as an oxidant, and hexamethylphosphoric triamine as a stabilizer. The reaction temperature is 80°C, and the reaction is carried out in a reaction solvent for 12 hours. After the reaction is completed, the indanone compound is obtained through post-treatment. This method can directly generate indanone compounds from amide-based heterocyclic compounds. It has the advantages of simple operation, short reaction time, and high reaction stability.

[0005] As a novel class of amide compounds, β-trifluoromethylthioamides still lack an effective method for synthesis, which severely restricts their application in medicinal chemistry research. Therefore, there is an urgent need for a method that can efficiently and concisely design and synthesize such compounds. Summary of the Invention

[0006] The purpose of this invention is to provide a method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol, which solves the problem of low synthesis efficiency of unsaturated amide compounds in the prior art.

[0007] A β-trifluoromethylthioamide, characterized by the following general molecular formula:

[0008]

[0009] The technical solution of the synthesis method of β-trifluoromethylthioamide involving silver trifluoromethylthiol provided by the present invention is as follows:

[0010] The specific steps of a method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol are as follows:

[0011] Step 1: Acrylamide, trifluoromethane mercaptan, acid and solvent are placed in a thick-walled pressure-resistant tube for reaction. The reaction time is 8 hours and the reaction temperature is 40-60℃.

[0012] Step 2: After the reaction is complete, dichloromethane is added to dilute the reaction solution, the organic solvent is removed by rotary evaporation, and the remaining product is separated by column chromatography to obtain β-trifluoromethylthio-saturated amide.

[0013] In step 1, the acrylamide is any one of N-(4-methoxyphenyl)-acrylamide, N-(2-methoxyphenyl)-acrylamide, N-(3-alkynylphenyl)-acrylamide, methyl 3-acrylamido-4-methylthiophene-2-carboxylate, N-(3-chloro-2-methylphenyl)-acrylamide, and N-(2-keto-benzofuranyl)-acrylamide.

[0014] Furthermore, in step 1, the mass ratio of acrylamide, silver trifluoromethane mercaptan, acid, and solvent is 1:2:1:4.

[0015] Furthermore, in step 1, the acid is any one of p-toluenesulfonic acid monohydrate, 5-sulfosalicylic acid 2H2O, and aluminum trifluoromethanesulfonate.

[0016] Furthermore, in step 1, the solvent is any one of tetrahydrofuran, toluene, acetonitrile, ethylene glycol dimethyl ether, and chlorobenzene.

[0017] Furthermore, in step 2, during column chromatography separation, a 200-300 mesh silica gel column is used for separation and purification.

[0018] Furthermore, in step 2, the eluent used during column chromatography is a mixture of petroleum ether and ethyl acetate.

[0019] The beneficial effects are: the present invention can achieve the preparation of β-trifluoromethylthio-saturated amide in only one step, the operation process is simple, and the reaction efficiency is effectively improved. In addition, the reaction temperature only needs to be 40-60℃, and it also has the advantages of low reaction energy consumption, low overall production cost, and high degree of technical and environmental friendliness. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below.

[0021] The method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol provided in this embodiment is implemented according to the following steps:

[0022] Step 1: Place acrylamide, trifluoromethane mercaptan, acid and solvent into a thick-walled pressure-resistant tube for reaction. The reaction time is 8 hours and the reaction temperature is 40-60℃.

[0023] The mass ratio of acrylamide, trifluoromethane mercaptan, silver trifluoromethane, acid, and solvent is 1:2:1:4.

[0024] Acrylamide is any one of N-(4-methoxyphenyl)-acrylamide, N-(2-methoxyphenyl)-acrylamide, N-(3-alkynylphenyl)-acrylamide, methyl 3-acrylamido-4-methylthiophene-2-carboxylate, N-(3-chloro-2-methylphenyl)-acrylamide, and N-(2-keto-benzofuranyl)-acrylamide.

[0025] The acid is any one of p-toluenesulfonic acid monohydrate, 5-sulfosalicylic acid 2H2O, and aluminum trifluoromethanesulfonate.

[0026] The solvent is any one of tetrahydrofuran, toluene, acetonitrile, ethylene glycol dimethyl ether, and chlorobenzene.

[0027] Step 2: After the reaction is complete, dilute the reaction solution with dichloromethane, remove the organic solvent by rotary evaporation, and separate and purify the remaining product by 200-300 mesh silica gel column to obtain β-trifluoromethylthio-saturated amide.

[0028] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent.

[0029] Example 1 of the method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethanethiol provided by the present invention is implemented according to the following steps: N-(4-methoxyphenyl)-acrylamide, silver trifluoromethanethiol, p-toluenesulfonic acid monohydrate and acetonitrile are placed in a thick-walled pressure-resistant tube for reaction for 8 hours at a reaction temperature of 40°C; after the reaction is completed, dichloromethane is added to dilute the reaction solution, the organic solvent is removed by rotary evaporation, and the remaining product is then separated and purified by a 200-300 mesh silica gel column to obtain N-(4-methoxyphenyl)-3-(trifluoromethylthio)-propionamide;

[0030] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 7:1 to 5:1; the data are as follows:

[0031] 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1 H), 7.30 (s, 1 H), 7.27 (s, 1H), 6.77 (s, 1 H), 6.75 (s, 1 H), 3.71 (s, 3 H), 3.13 (t, J = 7.0 Hz, 2 H),2.65 (t, J = 7.0 Hz, 2 H);

[0032] 13C NMR (101 MHz, CDCl3) δ 168.61, 156.75, 132.67, 130.44, 129.63,122.50, 114.10, 55.42, 36.89, 25.27;

[0033] 19F NMR (376 MHz, CDCl3) δ -41.23. (s, 3 F);

[0034] HRMS (ESI) m / z: [M+Na]+ calcd.for C 11 H 12 F3NNaO2S 302.0541; found:302.0525.

[0035] Example 2 of the method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol provided by the present invention is implemented according to the following steps:

[0036] N-(2-methoxyphenyl)-acrylamide, silver trifluoromethanethiol, p-toluenesulfonic acid monohydrate, and acetonitrile were placed in a thick-walled pressure-resistant tube and reacted for 8 hours at a temperature of 40°C. After the reaction was complete, dichloromethane was added to dilute the reaction solution, and the organic solvent was removed by rotary evaporation. The remaining product was then purified by separation using a 200-300 mesh silica gel column to obtain N-(2-methoxyphenyl)-3-(trifluoromethylthio)-propionamide.

[0037] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 7:1 to 1:1; the data are as follows:

[0038] 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1 H), 7.75 (s, 1 H), 7.01 (s, 1H), 6.91 (s, 1 H), 6.84 (s, 1 H), 3.84 (s, 3 H), 3.20 (s, 2 H), 2.78 (s, 2H);

[0039] 13C NMR (101 MHz, CDCl3) δ 167.79, 147.75, 135.75, 132.71, 129.67,127.20, 126.63, 124.05, 121.11, 119.88, 109.98, 55.70, 37.72, 25.16.;

[0040] 19F NMR (376 MHz, CDCl3) δ -40.96;

[0041] HRMS (ESI) m / z: [M+Na]+ calcd.for C11H12F3NNaO2S 302.0541; found:302.0528.

[0042] Example 3 of the specific embodiment of the method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol provided by the present invention is implemented according to the following steps:

[0043] This invention discloses a method for synthesizing β-trifluoromethylthioamide using silver trifluoromethylthiol, which is specifically implemented according to the following steps:

[0044] N-(3-alkynylphenyl)-acrylamide, trifluoromethane thiolate, p-toluenesulfonic acid monohydrate, and acetonitrile were placed in a thick-walled pressure-resistant tube and reacted for 8 hours at a temperature of 40°C. After the reaction was complete, dichloromethane was added to dilute the reaction solution, and the organic solvent was removed by rotary evaporation. The remaining product was then purified by separation using a 200-300 mesh silica gel column to obtain N-(3-alkynylphenyl)-3-(trifluoromethylthio)-propionamide.

[0045] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 12:1 to 10:1; the data are as follows:

[0046] 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1 H), 7.55 – 7.42 (m, 2 H), 7.24 (s, 1 H), 7.23 (s, 1 H), 3.20 (t, J = 6.8 Hz, 2 H), 3.04 (s, 1 H), 2.75 (t, J= 6.9 Hz, 2H);

[0047] 13C NMR (101 MHz, CDCl3) δ 162.86, 142.34, 129.99, 128.90, 128.63,128.57, 128.39, 127.02, 123.85, 121.17, 37.72;

[0048] 19F NMR (376 MHz, CDCl3) δ -65.00 (s, 3 F);

[0049] HRMS (ESI) m / z: [M+Na]+ calcd.for C 12 H 10 F3NNaOS 296.0435; found:296.0413.

[0050] Example 4 of the specific embodiment of the method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol provided by the present invention is implemented according to the following steps:

[0051] 3-Acrylamido-4-methylthiophene-2-carboxylate, silver trifluoromethanethiol, p-toluenesulfonic acid monohydrate, and acetonitrile were placed in a thick-walled pressure-resistant tube for 8 hours at a temperature of 40°C. After the reaction was complete, dichloromethane was added to dilute the reaction solution, and the organic solvent was removed by rotary evaporation. The remaining product was then purified by silica gel column chromatography using a 200-300 mesh filter to obtain 4-methyl-3-(3-trifluoromethylthiopropionamide)thiophene-2-carboxylate.

[0052] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 9:1 to 8:1; the data are as follows:

[0053] 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1 H), 7.09 (s, 1 H), 3.80 (s, 3H), 3.18 (s, 2 H), 2.82 (s, 2 H), 2.14 (s, 3 H);

[0054] 13C NMR (101 MHz, CDCl3) δ 168.19, 163.43, 142.09, 135.76, 132.47,129.42, 127.50, 117.31, 51.81, 36.63, 24.85, 15.44;

[0055] 19F NMR (376 MHz, CDCl3) δ -41.25.

[0056] HRMS (ESI) m / z: [M+Na]+ calcd.for C 11 H 12 F3NNaO3S 350.0211; found:350.0235.

[0057] Example 5 of the specific embodiment of the method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol provided by the present invention is implemented according to the following steps:

[0058] This invention discloses a method for synthesizing β-trifluoromethylthioamide using silver trifluoromethylthiol, which is specifically implemented according to the following steps:

[0059] N-(3-chloro-2-methylphenyl)-acrylamide, trifluoromethanethiol silver, p-toluenesulfonic acid monohydrate, and acetonitrile were placed in a thick-walled pressure-resistant tube and reacted for 8 hours at a temperature of 40°C. After the reaction was complete, dichloromethane was added to dilute the reaction solution, and the organic solvent was removed by rotary evaporation. The remaining product was then purified by silica gel column chromatography using a 200-300 mesh filter to obtain N-(3-chloro-2-methylphenyl)-3-(trifluoromethylthio)-propionamide.

[0060] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 10:1 to 8:1; the data are as follows:

[0061] 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1 H), 7.26 (s, 1 H), 7.23 (s, 1H), 7.10 (s, 1 H), 3.23 (s, 2 H), 2.80 (s, 2 H), 2.26 (s, 3 H);

[0062] 13C NMR (101 MHz, CDCl3) δ 168.65, 136.08, 135.69, 135.04, 132.65,129.60, 127.08, 126.84, 126.56, 123.26, 36.94, 25.30, 14.80;

[0063] 19F NMR (376 MHz, CDCl3) δ -41.03;

[0064] HRMS (ESI) m / z: [M+Na]+ calcd.for C 11 H 11 ClF3NNaOS 320.0202; found:320.0234.

[0065] Example 6 of the present invention provides a method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol, which is implemented according to the following steps:

[0066] N-(2-keto-benzofuranyl)-acrylamide, silver trifluoromethanethiol, p-toluenesulfonic acid monohydrate, and acetonitrile were placed in a thick-walled pressure-resistant tube for 8 hours at a temperature of 40°C. After the reaction was complete, dichloromethane was added to dilute the reaction solution, and the organic solvent was removed by rotary evaporation. The remaining product was then purified by silica gel column chromatography using a 200-300 mesh filter to obtain N-(2-keto-benzofuranyl)-3-(trifluoromethylthio)-propionamide.

[0067] During chromatographic separation, a mixture of petroleum ether and ethyl acetate was used as the eluent, with a petroleum ether:ethyl acetate ratio of 13:1 to 11:1; the data are as follows:

[0068] 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1 H), 7.40 (d, J = 10.8 Hz, 1 H), 7.25 – 7.17 (m, 1 H), 7.12 (dd, J = 8.1, 2.0 Hz, 1 H), 6.86 – 6.71 (m, 1 H), 3.19 (t, J = 6.8 Hz, 2 H), 2.77 (t, J = 6.9 Hz, 3 H);

[0069] 13C NMR (101 MHz, CDCl3) δ 168.45, 164.17, 161.73, 138.83, 138.73,135.66, 132.61, 130.24, 130.14, 129.57, 126.52, 115.32, 111.62, 107.79,37.44, 25.00;

[0070] 19F NMR (376 MHz, CDCl3) δ -41.29;

[0071] HRMS (ESI) m / z: [M+Na]+ calcd.for C 13 H 10 F3NNaO3S 340.0333; found:340.0312.

[0072]

[0073] Compound 1

[0074] 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1 H), 7.30 (s, 1 H), 7.27 (s, 1H), 6.77 (s, 1 H), 6.75 (s, 1 H), 3.71 (s, 3 H), 3.13 (t, J = 7.0 Hz, 2 H),2.65 (t, J = 7.0 Hz, 2 H); a

[0075] 13C NMR (101 MHz, CDCl3) δ 168.61, 156.75, 132.67, 130.44, 129.63,122.50, 114.10, 55.42, 36.89, 25.27;

[0076] 19F NMR (376 MHz, CDCl3) δ -41.23. (s, 3 F);

[0077] ​​​​​​​​​​​​​​​​​​​​​​​F3NNaO2S 302.0541; found: 302.0528.

[0083] Enclosure3

[0084] 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1 H), 7.55 – 7.42 (m, 2 H), 7.24(s, 1 H), 7.23 (s, 1 H), 3.20 (t, J = 6.8 Hz, 2 H), 3.04 (s, 1 H), 2.75 (t, 11). J= 6.9 Hz, 2 H)!

[0085] 13C NMR (101 MHz, CDCl3) δ 162.86, 142.34, 129.99, 128.90;

[0086] 19F NMR (376 MHz, CDCl3) δ-65.00 (s, 3F);

[0087] HRMS (ESI) m / z: [M+Na]+ calcd.for C 12 H 10 F3NNaOS 296.0435; found: 296.0413.

[0088] Enclosure4

[0089] 1H NMR (400 MHz, CDCl3) δ 8.74(s,1H), 7.09(s,1H), 3.80(s,3H), 3.18(s,2H), 2.82(s,2H), 2.14(s,3H)

[0090] 13C NMR (101 MHz, CDCl3) δ 168.19;

[0091] 19F NMR (376 MHz, CDCl3) δ-41.25.

[0092] HRMS (ESI) m / z: [M+Na]+ calcd.for C 11 H 12 F3NNaO3S 350.0211; found: 350.0235.

[0093] Enclosure5

[0094] 1H NMR (400 MHz, CDCl3) δ 7.47(s,1H), 7.26(s,1H), 7.23(s,1H), 7.10(s,1H), 3.23(s,2H), 2.80(s,2H), 2.26(s,3H)

[0095] 13C NMR (101 MHz, CDCl3) δ 168.65; 14.80.

[0096] 19F NMR (376 MHz, CDCl3) δ-41.03;

[0097] HRMS (ESI) m / z: [M+Na]+ calcd.for C 11 H 11 ClF3NNaOS 320.0202; found: 320.0234.

[0098] Enclosure6

[0099] 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1 H), 7.40 (d, J = 10.8 Hz, 1 H), 7.25 – 7.17 (m, 1 H), 7.12 (dd, J = 8.1, 2.0 Hz, 1 H), 6.86 – 6.71 (m, 1). H),3.19 (t, J = 6.8 Hz, 2 H), 2.77 (t, J = 6.9 Hz, 3 H)!

[0100] 13C NMR (101 MHz, CDCl3) δ 168.45, 164.17, 161.73, 138.83, 138.73,135.66, 132.61, 130.24, 130.14, 129.57, 126.52, 115.32, 111.62, 107.79,37.44, 25.00;

[0101] 19F NMR (376 MHz, CDCl3) δ -41.29;

[0102] HRMS (ESI) m / z: [M+Na]+ calcd.for C 13 H 10 F3NNaO3S 340.0333; found:340.0312.

Claims

1. A method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol, characterized in that, The specific steps of the method for synthesizing β-trifluoromethylthioamide are as follows: Step 1: Acrylamide, silver trifluoromethanethiol, acid, and solvent are placed in a thick-walled pressure-resistant tube for reaction. The reaction time is 8 hours, and the reaction temperature is 40-60℃. Step 2: After the reaction is complete, dichloromethane is added to dilute the reaction solution, the organic solvent is removed by rotary evaporation, and the remaining product is separated by column chromatography to obtain β-trifluoromethylthioamide. In Step 1, the acrylamide is any one of N-(4-methoxyphenyl)-acrylamide, N-(2-methoxyphenyl)-acrylamide, N-(3-alkynylphenyl)-acrylamide, methyl 3-acrylamido-4-methylthiophene-2-carboxylate, N-(3-chloro-2-methylphenyl)-acrylamide, and N-(2-keto-benzofuranyl)-acrylamide. In Step 1, the acid is any one of p-toluenesulfonic acid monohydrate, 5-sulfosalicylic acid 2H2O, and aluminum trifluoromethanesulfonate.

2. The method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol according to claim 1, characterized in that, In step 1, the mass ratio of acrylamide, silver trifluoromethane mercaptan, acid, and solvent is 1:2:1:

4.

3. The method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol according to claim 2, characterized in that, In step 1, the solvent is any one of tetrahydrofuran, toluene, acetonitrile, ethylene glycol dimethyl ether, and chlorobenzene.

4. The method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol according to any one of claims 1-3, characterized in that, In step 2, during column chromatography separation, a 200-300 mesh silica gel column is used for separation and purification.

5. The method for synthesizing β-trifluoromethylthioamide involving silver trifluoromethylthiol according to claim 4, characterized in that, In step 2, the eluent used during column chromatography is a mixture of petroleum ether and ethyl acetate.

Images