Preparation method of bromo-trifluoromethylthio acetophenone

Abstract

The invention discloses a preparation method of bromo-trifluoromethylthio acetophenone, and belongs to the field of chemical synthesis. According to the novel method for the brominated trifluoromethylthio-substituted bifunctionalization reaction of styrene, trifluoromethylthio silver and bromine water which are easy to obtain are adopted as a trifluoromethylthio source and a bromine source respectively, the substrate applicability is wide, and raw materials are simple and easy to obtain; in addition, according to the method, synthesis of the target product can be achieved only through 2-12 hours of reaction, the target product can be obtained with the good yield, and rapidness and high efficiency are achieved. According to the synthesis method disclosed by the invention, the bromo-trifluoromethylthio acetophenone compound is synthesized from simple and easily available aryl olefin under a relatively simple condition, so that bromo-trifluoromethylthio bifunctionalization of styrene is realized, and meanwhile, the fluorine-containing building block compound which is widely applied to the fields of medicines, pesticides and petrochemical engineering is converted.

Description

Technical Field

[0001] The invention specifically relates to a preparation method of brominated trifluoromethylthioacetophenone, and belongs to the field of chemical synthesis. Background Art

[0002] Since the discovery in the 1950s that the introduction of fluorine atoms into specific sites of drug molecules can improve their biological activity, a large number of fluorine-containing drugs have sprung up. From only 2% of the pharmaceutical market in 1970, it has reached about 20% today. In 2019, the US Food and Drug Administration (FDA) approved a total of 35 chemical drugs for marketing, of which 14 contained fluorine atoms and 7 contained trifluoromethylthio groups. In the past few decades, a large number of new and effective strategies for introducing SCF3 groups into organic molecules have been explored. Recently, due to the very important role of bromide in nucleophilic substitution and cross-coupling reactions, in the difunctionalization involving trifluoromethylthioation of unsaturated bonds, halogenated trifluoromethylthioation, especially the difunctionalization of bromotrifluoromethylthio substitution of alkenes and alkynes, has attracted great attention in the past few years.

[0003] Trifluoromethylthio has strong electron-withdrawing ability, high lipophilicity and metabolic stability. Introducing it into drug molecules can significantly change the physical and chemical properties and biological activity of the drugs, enhance the lipid solubility of drug molecules, make drugs more easily penetrate cell membranes, and enhance the transmembrane absorption of drug molecules. At the same time, it improves the metabolic stability of drug molecules and makes them less susceptible to oxidative degradation by oxidases in the body. Therefore, it has important value in the research and development of new drugs.

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

[0005]

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

[0007]

[0008] The overall yield of this method route is about 50% to 56%, but there are obvious defects: on the one hand, LDA, a dangerous and harsh reagent, must be used, an environment of minus 78°C is required, and high equipment requirements are required; on the other hand, the raw material 2-bromo-1-arylethanone is relatively expensive and not cheap and easy to obtain. Summary of the invention

[0009]

Technical issues

[0010] In order to solve the above problems, the present invention provides a new method for the difunctionalization reaction of bromotrifluoromethylthio substitution of styrene, that is, a method for preparing a bromotrifluoromethylthioacetophenone compound. The method uses styrene and trifluoromethylthiosilver, which are cheaper and more readily available, as substrates, and can achieve the difunctionalization reaction of bromotrifluoromethylthio substitution through a mild reaction process without harsh conditions under the action of an oxidant and a bromine source.

[0011]

Technical solution

[0012] The invention realizes the trifunctionalization reaction of the bromotrifluoromethylthio group of styrene by synthesizing a bromotrifluoromethylthioacetophenone compound through the reaction of an aromatic olefin and a trifluoromethylthio silver salt.

[0013] The object of the present invention is to provide a method for preparing a brominated trifluoromethylthioacetophenone compound, wherein the method comprises the following steps: in a solvent, an aromatic olefin compound represented by formula (1) and trifluoromethylthiosilver represented by formula (2) are used as substrates, and react under the action of an oxidant and a bromine source, and after the reaction is completed, a brominated trifluoromethylthio-substituted bifunctional compound of styrene represented by 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 amide groups, aryl groups.

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

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

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

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

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

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

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

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

[0024] In one embodiment of the present invention, 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.

[0025] In one embodiment of the present invention, the molar ratio of the oxidant to the aromatic olefin compound is (1.0-3.0):1. Specifically, it can be 1.5:1.

[0026] In one embodiment of the present invention, the steps of a novel green and economical preparation method are as follows:

[0027] The method comprises taking an aromatic olefin and trifluoromethylthiosilver as raw materials, stirring and reacting at 25° C.-85° C. for a period of time to obtain a crude product of a bromotrifluoromethylthioacetophenone compound, and then filtering, washing, vacuum distilling and column chromatography separation to obtain a pure bromotrifluoromethylthioacetophenone compound.

[0028] In the above method, the main separation method is rapid column chromatography separation to obtain the final product, bromotrifluoromethylthioacetophenone compound.

[0029] In one embodiment of the present invention, the method is preferably carried out in the following steps: adding aromatic olefin, silver trifluoromethylthio, potassium persulfate and bromine water in a molar ratio of 1:2:1.5:2 to a reaction vessel containing a dimethyl sulfoxide solvent, stirring at 25°C-85°C for 2-12 hours, separating and purifying to obtain the target product.

[0030] Beneficial effects:

[0031] The invention provides a method for preparing a brominated trifluoromethylthioacetophenone compound.

[0032] The method of the present invention uses an aromatic olefin compound as a substrate and trifluoromethylthiosilver as a trifluoromethylthiolation agent in an oxygen atmosphere, and under the action of an oxidant, the bromotrifluoromethylthiolation trifunctionalization of the aromatic olefin can be achieved in one step to obtain a target compound. The reaction mechanism of the present invention is as follows: trifluoromethylthiosilver is oxidized by potassium persulfate to generate a trifluoromethylthio free radical, the trifluoromethylthio free radical attacks and adds to the β position of styrene, the α position forms a free radical, combines with oxygen in potassium persulfate to form trifluoromethylthioacetophenone, and the α hydrogen of trifluoromethylthioacetophenone reacts with Br2 to generate bromotrifluoromethylthioacetophenone.

[0033] The method of the present invention uses easily available trifluoromethylthiosilver and bromine water as a trifluoromethylthio source and a bromine source, respectively, and has wide substrate applicability, simple and easily available raw materials, and low economic cost; in addition, the method of the present invention only needs 2-12 hours of reaction to achieve the synthesis of the target product, and the target product can be obtained with a good yield, which is faster and more efficient.

[0034] The synthesis method of the invention uses easily available aromatic olefins to synthesize brominated trifluoromethylthioacetophenone compounds under relatively simple conditions, realizes the difunctionalization of brominated trifluoromethylthio groups of styrene and simultaneously converts them into fluorine-containing building block compounds that are widely used in the fields of medicine, pesticides and petrochemicals. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The synthetic route diagram of the method of the present invention is shown in FIG. DETAILED DESCRIPTION

[0036] The following are specific embodiments of the present invention.

[0037] The synthetic route diagram of the embodiment of the present invention is as follows: Figure 1 As shown:

[0038] Aromatic olefin and trifluoromethylthiosilver are used as raw materials, potassium persulfate is used as an oxidant and added to a reaction bottle containing dimethyl sulfoxide, and then the reaction bottle is placed in a 25℃-85℃ oil bath pot to fully react 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), trifluoromethylthiosilver (416 mg, 2.0 mmol), potassium persulfate (405 mg, 1.5 mmol) and bromine water (318 mg, 2.0 mmol) were added respectively, and after oxygen substitution, the mixture was fully reacted in 10 ml chloroform at 40°C for 6 hours. After the reaction was completed, the mixture 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, concentrated again, and purified by column chromatography to obtain 195 mg of the target product with a yield of 55%.

[0041] 1 H NMR (400MHz, CDCl3) δ8.12-7.79(m,1H),7.57-7.52(m,1H),6.66(s,1H),1.36(s,5H). 13 C NMR (101MHz, CDCl3) δ187.38 (s), 159.23 (s), 129.62 (q, J = 309.3Hz), 129.5 0(s),128.74(s),126.18(s),47.90(q,J=4.5,2.2Hz),35.43(s),30.97(s). 19 F NMR(376MHz, CDCl3)δ-41.10(s).

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

[0043] In a 25 ml reaction tube equipped with a rotor, p-methylstyrene (118 mg, 1 mmol), trifluoromethylthiosilver (416 mg, 2.0 mmol), potassium persulfate (405 mg, 1.5 mmol) and bromine water (318 mg, 2.0 mmol) were added respectively, and after oxygen substitution, the mixture was fully reacted in 10 ml chloroform at 40°C for 6 hours. After the reaction was completed, the mixture 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, concentrated again, and purified by column chromatography to obtain 156 mg of the target product with a yield of 50%.

[0044] 1 H NMR (400MHz, CDCl3) δ7.92 (d, J = 8.3Hz, 1H), 7.34 (d, J = 8.0Hz, 1H), 6.64 (s, 1H), 2.46 (s, 2H). 13C NMR (101MHz, CDCl3) δ187.19(s), 146.50(s), 129.90(s), 129.74(s), 129.68(q,J=309.1Hz), 129.08(s), 62.00(q,J=4.5,2.2Hz), 21.89(s). 19 F NMR(376MHz, CDCl3)δ-40.54(s).

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

[0046] In a 25 ml reaction tube equipped with a rotor, p-methoxystyrene (134 mg, 1 mmol), trifluoromethylthiosilver (416 mg, 2.0 mmol), potassium persulfate (405 mg, 1.5 mmol) and bromine water (318 mg, 2.0 mmol) were added respectively, and after oxygen substitution, the mixture was fully reacted in 10 ml chloroform at 40°C for 6 hours. After the reaction, the mixture 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, concentrated again, and purified by column chromatography to obtain 190 mg of the target product with a yield of 58%.

[0047] 1 H NMR (400MHz, CDCl3) δ8.03-7.97(m,1H),7.05-6.93(m,1H),6.64(d,J=4.6Hz,1H),3.90(s,1H). 13 C NMR (101MHz, CDCl3) δ186.12(s), 165.11(s), 132.17(s), 129.74(q, J=309.1Hz), 124.30(s), 114.49(s), 62.07(dd, J=4.4, 2.2Hz), 55.73(s). 19 F NMR(376MHz, CDCl3)δ-40.57(s).

[0048] Example 4 Investigating the Effect of Bromine Source on the Synthesis of Bromotrifluoromethylthioacetophenone

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

[0050] Table 1 Effect of different bromine sources on the synthesis of brominated trifluoromethylthioacetophenone

[0051] Bromine source Yield (%) <![CDATA[CuBr2]]> 0 <![CDATA[FeBr3]]> 0 NBS 10

[0052] The results show that when copper bromide, iron bromide and NBS are used to replace the bromine water in Example 2 as the bromine source, the yield of the obtained product is lower than that of Example 1, and the yield does not exceed 15%.

[0053] Example 5: Effect of solvent selection on the synthesis of trifluoromethylthiobromoacetophenone

[0054] Referring to Example 1, the solvent was replaced by acetonitrile, toluene, and dimethyl sulfoxide respectively from chloroform, and other conditions remained unchanged to obtain the corresponding bromotrifluoromethylthioacetophenone.

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

[0056] Table 2 Effect of different solvents on the synthesis of trifluoromethylthioaryl sulfide

[0057] Solvents Yield (%) DMSO 25 DMF 15 <![CDATA[CH3CN]]> 35 Toluene 22 THF 0

[0058] The results show that when acetonitrile, toluene or dimethyl sulfoxide is used as the solvent instead of chloroform in Example 2, the yield of the product obtained is lower than that of Example 1, and the yield does not exceed 40%.

Claims

1. A method for preparing a brominated trifluoromethylthioacetophenone compound, characterized in that: The method comprises the following steps: in a solvent, an aromatic olefin compound represented by formula (1) and trifluoromethylthiosilver represented by formula (2) are used as substrates, and react under the action of an oxidant and a bromine source to obtain a bifunctional compound represented by formula (3) substituted with bromotrifluoromethylthio of styrene; Wherein, R is selected from H, C 1-6 Alkyl, halogen (F, Cl, Br, I), cyano, nitro, C 1-6 Alkoxy, acyl and amide groups, aryl groups.

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

3. The method according to claim 1, characterized in that The solvent is chloroform.

4. The method according to claim 1, characterized in that: The bromine source is bromine water.

5. The method according to claim 1, characterized in that 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.

6. The method according to claim 1, characterized in that The molar ratio of the trifluoromethylthiosilver to the aromatic olefin compound is (1.5-3):

1.

7. The method according to claim 1, characterized in that The molar ratio of the bromine source to the aromatic olefin compound is (1.0-2.5):

1.

8. The method according to claim 1, characterized in that The molar ratio of the oxidant to the aromatic olefin compound is (1.0-3.0):

1.

9. The method according to claim 1, characterized in that: The reaction temperature is 25°C-85°C.

10. The method according to any one of claims 1 to 9, characterized in that: The reaction time is 2-12 hours.

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