A method for preparing a bromotrifluoromethylsulfinylacetophenone

Abstract

The application discloses a preparation method of bromo-trifluoromethylthioacetophenone and belongs to the field of chemical synthesis. The application provides a novel method for the bromo-trifluoromethylthio substitution of the bifunctionalization reaction of styrene, and the easily obtained trifluoromethylthio silver and bromine water are used as the trifluoromethylthio source and the bromine source, respectively, the substrate has wide applicability, and the raw material is simple and easy to obtain. In addition, the method can realize the synthesis of the target product, and the target product can be obtained in a good yield in 2-12 hours, and the method is more rapid and efficient. The synthesis method can synthesize the bromo-trifluoromethylthioacetophenone compound under relatively simple conditions by using the simple and easily obtained aryl olefin, realizes the bromo-trifluoromethylthio bifunctionalization of the styrene, and converts the styrene into the fluorine-containing building block compound which has wide application in the fields of medicine, pesticide and petroleum chemical industry.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing bromo-trifluoromethylthioacetophenone, and belongs to the field of chemical synthesis. BACKGROUND

[0002] Since the 1950s, when it was discovered that introducing fluorine atoms into specific positions of drug molecules could improve their biological activity, a large number of fluorine-containing drugs have emerged like mushrooms after rain. From 1970, only 2% of the pharmaceutical market, to now about 20%. In 2019, the US Food and Drug Administration (FDA) approved 35 chemical drugs for marketing, of which 14 contained fluorine atoms, and 7 contained trifluoromethylthio groups. In the past few decades, people have explored a large number of new and effective strategies for introducing SCF3 groups into organic molecules. Recently, due to the very important role of bromide in nucleophilic substitution and cross-coupling reactions, in the bifunctionalization of trifluoromethylthiolation involving unsaturated bonds, halogen trifluoromethylthiolation, especially the bifunctionalization of bromo-trifluoromethylthio substitution of alkenes and alkynes, has attracted great attention in the past few years.

[0003] Trifluoromethylthio groups have strong electron-withdrawing ability, high lipophilicity and metabolic stability. Introducing them into drug molecules can significantly change the physicochemical properties and biological activity of drugs, enhance the lipophilicity of drug molecules, make drugs more easily penetrate cell membranes, improve the transmembrane absorption of drug molecules, and improve the metabolic stability of drug molecules, not easily oxidized and degraded by oxidases in the body. Therefore, it has important value in the research and development of new drugs.

[0004] For example, the prior art (Mild Darzens Annulations for the Assembly of Trifluoromethylthiolated (SCF3) Aziridine and Cyclopropane Structures. Org. Lett. 2021, 23, 6121-6125.) reports the synthesis of a trifluoromethylthio aziridine cyclopropane compound. These trifluoromethylthio aziridine cyclopropane structures can be further applied in the fields of pharmaceuticals and agrochemicals.

[0005]

[0006] The important synthetic intermediate structure of the above-mentioned trifluoromethylthio aziridine cyclopropane active compound is The current synthesis method of the intermediate is as reported in the existing literature (Electrophilic Trifluoromethylthiolation of Carbonyl Compounds. Chem. Eur. J. 2014, 20, 1-6.), and the corresponding synthetic route is as shown below:

[0007]

[0008] The overall yield of the method route is about 50% to 56%, but there are obvious defects: on the one hand, the dangerous and harsh reagent LDA needs to be used, which requires a zero environment of minus 78℃ and high requirements for equipment; on the other hand, the raw material 2-bromo-1-aryl ethanone is not cheap and easy to obtain. SUMMARY

[0009] TECHNICAL PROBLEM

[0010] In order to solve the above problems, the present application provides a new method for bromo-trifluoromethylthio substitution of bifunctionalization of styrene, that is, a preparation method of bromo-trifluoromethylthioacetophenone compound. The method uses more cheap and easy to obtain styrene and trifluoromethylthio silver as the substrate, under the action of oxidant and bromine source, without harsh conditions, through a mild reaction process, the bromo-trifluoromethylthio substitution of bifunctionalization reaction can be realized.

[0011] TECHNICAL SCHEME

[0012] The present application realizes the bromo-trifluoromethylthio trifunctionalization reaction of styrene by selecting the reaction of aryl olefin and trifluoromethylthio silver salt to synthesize bromo-trifluoromethylthioacetophenone compound.

[0013] The purpose of the present application is to provide a preparation method of bromo-trifluoromethylthioacetophenone compound, wherein the aryl olefin compound shown in formula (1) and the trifluoromethylthio silver shown in formula (2) are used as the substrate, and the reaction occurs under the action of oxidant and bromine source, and after the reaction is completed, the bromo-trifluoromethylthio substitution of bifunctionalization compound of styrene shown in formula (3) is obtained.

[0014]

[0015] wherein R is selected from H, C 1-6 alkyl, halogen (F, Cl, Br, I), cyano, nitro, C 1-6 alkoxy, acyl and amido, aryl.

[0016] In an embodiment of the present application, the acyl group is -COR1, and R1 is selected from C 1-6 alkyl.

[0017] In one embodiment of the present application, the amido group is -NR2COR3, R2 is selected from H, C 1-6 alkyl, and R3 is selected from C 1-6 alkyl.

[0018] In one embodiment of the present application, the solvent is chloroform.

[0019] In one embodiment of the present application, the reaction temperature is 25-85°C.

[0020] In one embodiment of the present application, the reaction time is 2-12 hours.

[0021] In one embodiment of the present application, the molar ratio of the silver trifluoromethylthio to the aryl olefin compound is (1.5-3):1. Specifically, 2:1 can be selected.

[0022] In one embodiment of the present application, the bromine source is bromine water.

[0023] In one embodiment of the present application, the molar ratio of the bromine source to the aryl olefin compound is (1.0-2.5):1. Specifically, 2:1 can be selected.

[0024] In one embodiment of the present application, the oxidizing agent is selected from any one or more of the following: potassium persulfate, sodium persulfate, potassium iodate, sodium iodate, potassium periodate, sodium periodate, oxygen.

[0025] In one embodiment of the present application, the molar ratio of the oxidizing agent to the aryl olefin compound is (1.0-3.0):1. Specifically, 1.5:1 can be selected.

[0026] In one embodiment of the present application, a novel green and economic preparation method is as follows:

[0027] The aryl olefin and silver trifluoromethylthio are used as raw materials, and after stirring at 25-85°C for a period of time, a crude product of bromo-trifluoromethylthio-acetophenone compound is obtained, and then the pure bromo-trifluoromethylthio-acetophenone compound is obtained by filtration, washing, reduced pressure distillation and column chromatography separation.

[0028] In the above method, the main separation method is rapid column chromatography separation, and the final product bromo-trifluoromethylthio-acetophenone compound is obtained.

[0029] In one embodiment of the present application, the method is preferably carried out by the following steps: aryl olefin, silver trifluoromethylthio, potassium persulfate, bromine water are added to a reaction container containing dimethyl sulfoxide solvent in a molar ratio of 1:2:1.5:2, stirring at 25-85°C for 2-12 hours, and then the target product is obtained by separation and purification.

[0030] Advantages:

[0031] The application provides a preparation method of a bromotrifluoromethylthioacetophenone compound.

[0032] The method of the application can realize bromotrifluoromethylthio trifunctionalization of an aryl olefin in one step under the action of an oxidant, to obtain the target compound, by taking the aryl olefin compound as a substrate and taking trifluoromethylthio silver as a trifluoromethylthio reagent in an oxygen atmosphere. The reaction mechanism of the application is as follows: the trifluoromethylthio silver is oxidized by potassium persulfate to generate a trifluoromethylthio radical, the trifluoromethylthio radical attacks and adds to the beta position of the styrene, the alpha position forms a radical, and is combined with oxygen in the potassium persulfate to form a trifluoromethylthioacetophenone, and the alpha hydrogen of the trifluoromethylthioacetophenone reacts with Br2 to generate a bromotrifluoromethylthioacetophenone.

[0033] The method of the application uses easily available trifluoromethylthio silver and bromine water as the trifluoromethylthio source and the bromine source, respectively, has wide substrate applicability, simple and easily available raw materials, and low economic cost; in addition, the method of the application can realize synthesis of the target product, and the target product can be obtained in a good yield in only 2-12 hours, which is more rapid and efficient.

[0034] The synthesis method of the application can synthesize the bromotrifluoromethylthioacetophenone compound from the simple and easily available aryl olefin under relatively simple conditions, realizes bromotrifluoromethylthio double functionalization of the styrene, and converts the styrene into a fluorine-containing building block compound which has wide application in the fields of medicine, pesticide and petroleum chemical industry. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The synthesis route map of the method of the application is shown. DETAILED DESCRIPTION

[0036] The following is a specific embodiment of the application.

[0037] The synthesis route map of the embodiment of the application is shown in Figure 1 .

[0038] The aryl olefin and the trifluoromethylthio silver are used as raw materials, the potassium persulfate is used as an oxidant and is added to a reaction bottle containing dimethyl sulfoxide, and then the reaction bottle is placed in a 25-85 DEG C oil bath for sufficient reaction for 2-12 hours. The reaction expression is Figure 1 .

[0039] Example 1: Synthesis of 2-bromo-2-(trifluoromethylthio) p-tert-butylacetophenone

[0040] In a 25 ml reaction tube equipped with a rotor, p-tert-butylstyrene (160 mg, 1 mmol), silver trifluoromethylsulfide (416 mg, 2.0 mmol), potassium persulfate (405 mg, 1.5 mmol), and bromine water (318 mg, 2.0 mmol) were added, and after oxygen replacement, it was sufficiently reacted for 6 hours at 40°C in 10 ml of chloroform. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated sodium chloride solution, respectively, concentrated in vacuo, and dried with anhydrous magnesium sulfate, and the target was purified by column chromatography after re-concentration, and 195 mg of the target was obtained at a yield of 55%.

[0041] 1 H NMR (400 MHz, CDCl3) δ 8.12-7.79 (m, 1H), 7.57-7.52 (m, 1H), 6.66 (s, 1H), 1.36 (s, 5H). 13 C NMR (101 MHz, CDCl3) δ 187.38 (s), 159.23 (s), 129.62 (q, J = 309.3 Hz), 129.50 (s), 128.74 (s), 126.18 (s), 47.90 (q, J = 4.5, 2.2 Hz), 35.43 (s), 30.97 (s). 19 F NMR (376 MHz, CDCl3) δ -41.10 (s).

[0042] Example 2: Synthesis of 2-bromo-2-(trifluoromethylsulfanyl) p-methylacetophenone

[0043] In a 25 ml reaction tube equipped with a rotor, p-tert-butylstyrene (160 mg, 1 mmol), silver trifluoromethylsulfide (416 mg, 2.0 mmol), potassium persulfate (405 mg, 1.5 mmol), and bromine water (318 mg, 2.0 mmol) were added, and after oxygen replacement, it was sufficiently reacted for 6 hours at 40°C in 10 ml of chloroform. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water and saturated sodium chloride solution, respectively, concentrated in vacuo, and dried with anhydrous magnesium sulfate, and the target was purified by column chromatography after re-concentration, and 195 mg of the target was obtained at a yield of 55%.

[0044] 1 H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.64 (s, 1H), 2.46 (s, 2H). 13C NMR (101 MHz, CDCI3) δ 187.19 (s), 146.50 (s), 129.90 (s), 129.74 (s), 129.68 (q, J = 309.1 Hz), 129.08 (s), 62.00 (q, J = 4.5, 2.2 Hz), 21.89 (s). 19 F NMR (376 MHz, CDCI3) δ -40.54 (s).

[0045] Example 3: Synthesis of 2-bromo-2-(trifluoromethylthio) p-methoxyacetophenone

[0046] Into a 25 ml reaction tube with a rotor, p-methoxy styrene (134 mg, 1 mmol), trifluoromethylthio silver (416 mg, 2.0 mmol), potassium persulfate (405 mg, 1.5 mmol) and bromine water (318 mg, 2.0 mmol) were added respectively, oxygen was replaced, and after 6 hours of reaction at 40 °C in 10 ml of chloroform, the reaction was cooled to room temperature, diluted with ethyl acetate and washed with distilled water and saturated sodium chloride solution respectively, concentrated in vacuum and dried with anhydrous magnesium sulfate, the target product was purified by column chromatography again, and 190 mg of the target product was obtained with a yield of 58%.

[0047] 1 H NMR (400 MHz, CDCI3) δ 8.03-7.97 (m, 1H), 7.05-6.93 (m, 1H), 6.64 (d, J = 4.6 Hz, 1H), 3.90 (s, 1H). 13 C NMR (101 MHz, CDCI3) δ 186.12 (s), 165.11 (s), 132.17 (s), 129.74 (q, J = 309.1 Hz), 124.30 (s), 114.49 (s), 62.07 (dd, J = 4.4, 2.2 Hz), 55.73 (s). 19 F NMR (376 MHz, CDCI3) δ -40.57 (s).

[0048] Example 4: Influence of bromine source on the synthesis of bromo-trifluoromethylthioacetophenone

[0049] Referring to Example 1, the bromine source was replaced by copper bromide, iron bromide and NBS respectively, and the other conditions were unchanged, and the corresponding bromo-trifluoromethylthioacetophenone was prepared. The specific yield results are shown in Table 1.

[0050] Table 1 Influence of different bromine sources on the synthesis of bromo-trifluoromethylthioacetophenone

[0051] Bromine source Yield (%) [CuBr2] 0 FeBr3 0 NBS 10

[0052] The results show that: using copper bromide, iron bromide, NBS instead of bromine water in example 2 as bromine source, the yield of the product is worse than example 1, the yield is not more than 15%.

[0053] Example 5 explores the effect of solvent selection on the synthesis of bromotri fluoromethylthioacetophenone

[0054] Referring to example 1, the solvent is replaced by acetonitrile, toluene, dimethyl sulfoxide respectively instead of chloroform, and other conditions remain unchanged, the corresponding bromotri fluoromethylthioacetophenone is prepared.

[0055] The specific yield results are shown in table 2.

[0056] Table 2 effect of different solvents on the synthesis of trifluoromethylthio aryl sulfide

[0057] Solvent Yield (%) DMSO 25 DMF 15 CH3CN 35 Toluene 22 THF 0

[0058] It is found that: using acetonitrile, toluene, dimethyl sulfoxide instead of chloroform in example 2 as solvent, the yield of the product is worse than example 1, the yield is not more than 40%.

Claims

1. A method for preparing a bromotrifluoromethylthioacetophenone compound, characterized in that, The method involves reacting an aryl olefin compound of formula (1) and a trifluoromethylthiosilver of formula (2) as substrates in a solvent under the action of an oxidant and a bromine source to obtain a brominated trifluoromethylthiolated difunctionalized compound of styrene of formula (3). Among them, R is selected from H and C. 1-6 Alkyl, halogen, cyano, nitro, C 1-6 Alkoxy, acyl and amide groups, aryl; The solvent is trichloromethane; The bromine source is bromine water; The oxidant is selected from any one or more of the following: potassium persulfate, sodium persulfate, potassium iodate, sodium iodate, potassium periodate, sodium periodate, and oxygen; The molar ratio of the trifluoromethyl thiosilver to the aryl olefin compound is (1.5~3):1; The molar ratio of the bromine source to the aryl olefin compound is (1.0 - 2.5):1; The molar ratio of the oxidant to the aryl olefin compound is (1.0 - 3.0):1; The reaction temperature is 25℃ - 85℃.

2. The method according to claim 1, characterized in that, The acyl group is -COR1, and R1 is selected from C 1-6 Alkyl group; amide group is -NR2COR3, R2 is selected from H, C 1-6 Alkyl group, R3 is selected from C 1-6 alkyl.

3. The method according to claim 1, characterized in that, The molar ratio of the trifluoromethylthiosilver to the aryl olefin compound is 2:

1.

4. The method according to claim 1, characterized in that, The molar ratio of the bromine source to the aryl olefin compound is 2:

1.

5. The method according to claim 1, characterized in that, The molar ratio of the oxidant to the aryl olefin compound is 1.5:

1.

6. The method according to any one of claims 1-5, characterized in that, The reaction time is 2-12 hours.

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