Polyfluoro aryl substituted sulfone compound and synthesis method and application thereof

Abstract

The invention discloses a polyfluorinated aryl substituted sulfone compound and a synthetic method and application thereof, the chemical structural formula of the polyfluorinated aryl substituted sulfone compound is # imgabs0. According to the synthetic method provided by the invention, under the photocatalytic condition, a polyfluorinated aromatic hydrocarbon compound, DABSO and potassium alkyl trifluoroborate are directly used as synthetic raw materials, and a higher yield can be obtained at normal temperature; the method is simple in process, environment-friendly and high in atom utilization rate, conforms to the green chemistry concept, and has excellent catalytic synthesis value and industrial application potential.

Description

Technical Field

[0001] The invention relates to the technical field of sulfone compounds, and in particular to a polyfluoroaryl substituted sulfone compound and a synthesis method and application thereof. Background Art

[0002] Polyfluoroaryl sulfone compounds have unique biological and pharmacological activities and are widely present in bioactive molecules and drug molecules ( like The following formula middle A Said ). For example, ciprofloxacin A derived from polyfluoroaryl sulfone has good antibacterial activity (Heterocyclic Chem., 2015, 53, 89); polyfluoroaryl sulfonamide B can be used as a carbonic anhydrase inhibitor (Bioorg. Med. Chem., 2013, 21, 2093); perfluoroaryl sulfonamide C can be used as an antitumor drug, etc. (Proc. Natl. Acad. Sci. USA, 1999, 96, 5686). At the same time, polyfluoroaryl sulfone compounds also have important applications in materials chemistry such as molecular adsorption, polymer photocatalysts and other fields. Therefore, it is of great value to develop new synthesis methods for polyfluoroaryl sulfone compounds.

[0003] A Bioactive and Drug Molecules Containing Polyfluoroarylsulfone Skeletons

[0004]

[0005] B. Traditional method for synthesizing polyfluoroaryl sulfone compounds

[0006]

[0007] The above is the importance and synthesis method of polyfluoroaryl sulfone compounds

[0008] The traditional synthesis method of polyfluoroaryl sulfone compounds is based on a two-step synthesis method ( As in the formula B Shown ). 1. Use liquid bromine and fuming nitric acid to achieve the oxidation of polyfluoroaryl thiols to synthesize polyfluoroaryl sulfonyl bromides, and then obtain polyfluoroaryl sulfone skeletons through tandem functionalization (Russ. J. Org. Chem., 2011, 47, 374; Procedia Chem., 2015, 15, 265). 2. The nucleophilic substitution and tandem oxidation process of thiols / thiophenols and polyfluoroaromatic hydrocarbons can also achieve the synthesis of polyfluoroaryl sulfones. The above strategy provides a method for the synthesis of important polyfluoroaryl sulfone compounds, but there are still problems such as cumbersome operation and poor functional group compatibility that need to be solved. Summary of the invention

[0009] The present invention provides a three-component synthesis method of polyfluoroaryl substituted sulfone compounds under mild conditions. Under photocatalytic conditions, polyfluoroaryl compounds, DABSO and potassium alkyl trifluoroborate are directly used as synthesis raw materials. The reaction conditions are mild, energy-saving and environmentally friendly, and no additional reducing agent or base is required to be added, so that the system is relatively simple, and the method has excellent catalytic synthesis value and industrial application potential.

[0010] The present invention is achieved through the following technical solutions:

[0011] In the first aspect, the present invention provides a polyfluoroaryl substituted sulfone compound, the chemical structure of which is:

[0012]

[0013] in:

[0014] OR1 includes methoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, and an alkoxy group derived from menthol, fructose diacetone, and gingerone;

[0015] R2 includes one of cyano, trifluoromethyl, and ketocarbonyl;

[0016] R3 includes one of tert-butyl, isopropyl, ethyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, and substituted or unsubstituted benzyl.

[0017] The polyfluoroaryl substituted sulfone compound provided by the present invention is a white solid, which can be separated from the reaction system by a column chromatography method, and can be comprehensively characterized by a nuclear magnetic resonance hydrogen spectrum, a nuclear magnetic resonance carbon spectrum, a nuclear magnetic resonance fluorine spectrum and a high-resolution mass spectrum.

[0018] In a second aspect, the present invention provides a method for synthesizing a polyfluoroaryl substituted sulfone compound, which is used to prepare the above-mentioned polyfluoroaryl substituted sulfone compound, comprising the steps of:

[0019] In an inert atmosphere, under the action of a photocatalyst, the reaction materials are irradiated with visible light in a solvent to undergo a photocatalytic reaction to prepare a polyfluoroaryl substituted sulfone compound;

[0020] The reaction materials include polyfluoroaromatic compounds, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct (DABSO), and alkyl potassium trifluoroborate.

[0021] The present invention realizes the synthesis of polyfluoroaryl-substituted sulfone compounds using polyfluoroaromatic compounds, DABSO and potassium alkyl trifluoroborate as raw materials under photocatalytic conditions. Compared with the traditional heating reaction, the visible light catalytic reaction has the advantages of simple experimental operation, mild conditions, high functional group tolerance, wide application range, energy saving and environmental protection. The present invention does not need to add additional reducing agents, organic bases or inorganic bases, the reaction process can occur at room temperature, and has a high yield and high atomic utilization, which is in line with the synthesis concept of green chemistry. The present invention has been successfully applied to the synthesis of various polyfluoroaryl-substituted sulfone compounds, showing excellent catalytic synthesis value and industrial application potential.

[0022] In a third aspect, the present invention provides the use of the polyfluoroaryl substituted sulfone compounds or the polyfluoroaryl substituted sulfone compounds synthesized by the above-mentioned synthesis method in the field of medicine.

[0023] The present invention provides the above-mentioned polyfluoroaryl substituted sulfone compounds, which can be applied to the later modification of drug active molecules.

[0024] The present invention can synthesize the following polyfluoroaryl substituted sulfone compounds:

[0025]

[0026] 4ea is the corresponding ester containing menthol structure. Menthol can be used as a flavoring agent for toothpaste, perfume, beverages and candies. It is used as a stimulant in medicine, acting on the skin or mucous membrane, and has a cooling and antipruritic effect. It can be taken orally as a carminative for headaches and inflammation of the nose, pharynx and throat. The present invention can modify natural products such as menthol or active pharmaceutical molecules to synthesize polyfluoroaryl substituted sulfone compounds such as 4ea.

[0027] The present invention has the following advantages and beneficial effects:

[0028] The present invention uses polyfluoroaromatic compounds, DABSO and potassium alkyl trifluoroborate as raw materials at room temperature, without adding additional reducing agents or bases, to react and prepare polyfluoroaryl substituted sulfone compounds. The technology of the present invention has the following significant advantages:

[0029] 1. The present invention uses polyfluoroaryl sulfone, DABSO and potassium alkyl trifluoroborate to synthesize polyfluoroaryl sulfone skeletons in one step under visible light catalysis. Visible light is an abundant, green, pollution-free and recyclable natural resource. The use of visible light to prepare polyfluoroaryl substituted sulfone compounds has the advantages of green energy saving and environmental protection, and meets the requirements of green chemistry and sustainable development.

[0030] 2. The present invention does not require the addition of additional reducing agents or alkalis, is easy to operate, and has a relatively simple reaction system.

[0031] 3. The synthesis method provided by the present invention can be carried out at room temperature, without the need for high temperature, and the reaction conditions are mild.

[0032] 4. The synthesis method provided by the present invention can obtain the corresponding products with excellent yields for polyfluoroaromatic substrates containing methyl, isopropyl, tert-butyl, phenyl, benzyl, etc., shows excellent functional group tolerance, has a wide range of applications, has excellent catalytic synthesis value and industrial application potential, and provides a new method for the synthesis of polyfluoroaromatic substituted sulfone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The drawings described herein are used to provide a further understanding of the embodiments of the present invention, constitute a part of this application, and do not constitute a limitation of the embodiments of the present invention. In the drawings:

[0034] Figure 1 This is the H NMR spectrum of the polyfluoroaryl substituted sulfone compound 4aa provided in the example.

[0035] Figure 2 This is the NMR carbon spectrum of the polyfluoroaryl substituted sulfone compound 4aa provided in the example.

[0036] Figure 3 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4aa provided in the example.

[0037] Figure 4 This is the H NMR spectrum of the polyfluoroaryl substituted sulfone compound 4ba provided in the example.

[0038] Figure 5 This is the NMR carbon spectrum of the polyfluoroaryl substituted sulfone compound 4ba provided in the example.

[0039] Figure 6 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4ba provided in the example.

[0040] Figure 7 This is the H NMR spectrum of the polyfluoroaryl substituted sulfone compound 4ca provided in the example.

[0041] Figure 8 This is the NMR carbon spectrum of the polyfluoroaryl substituted sulfone compound 4ca provided in the example.

[0042] Fig. 9 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4ca provided in the example.

[0043] Fig.10 This is the H NMR spectrum of the polyfluoroaryl substituted sulfone compound 4da provided in the example.

[0044] Fig.11This is the NMR carbon spectrum of the polyfluoroaryl substituted sulfone compound 4da provided in the example.

[0045] Fig.12 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4da provided in the example.

[0046] Fig.13 This is the H-NMR spectrum of the polyfluoroaryl substituted sulfone compound 4ab provided in the example.

[0047] Fig.14 This is the carbon NMR spectrum of the polyfluoroaryl substituted sulfone compound 4ab provided in the example.

[0048] Fig.15 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4ab provided in the example.

[0049] Fig.16 This is the H NMR spectrum of the polyfluoroaryl substituted sulfone compound 4ea provided in the example.

[0050] Fig.17 This is the NMR carbon spectrum of the polyfluoroaryl substituted sulfone compound 4ea provided in the example.

[0051] Fig.18 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4ea provided in the example. Fig.19 This is the NMR fluorine spectrum of the polyfluoroaryl substituted sulfone compound 4ea provided in the example. DETAILED DESCRIPTION

[0052] In order to make the objectives, technical solutions and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with embodiments and drawings. The exemplary embodiments of the present invention and their description are only used to explain the present invention and are not intended to limit the present invention.

[0053] The present invention provides a polyfluoroaryl substituted sulfone compound, the chemical structure of which is:

[0054]

[0055] in:

[0056] OR1 includes methoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, and an alkoxy group derived from menthol, fructose diacetone, and gingerone;

[0057] R2 includes one of cyano, trifluoromethyl, and ketocarbonyl;

[0058] R3 includes one of tert-butyl, isopropyl, ethyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, and substituted or unsubstituted benzyl.

[0059] The present invention provides a method for synthesizing a polyfluoroaryl substituted sulfone compound, which is used to prepare the above-mentioned polyfluoroaryl substituted sulfone compound, comprising the steps of:

[0060] In an inert atmosphere, under the action of a photocatalyst, the reaction materials are irradiated with visible light in a solvent to undergo a photocatalytic reaction to prepare a polyfluoroaryl substituted sulfone compound;

[0061] The reaction materials include polyfluoroaromatic compounds, DABSO, and alkyl potassium trifluoroborate.

[0062] This application uses cheap and readily available SO 2 / SO 2 Substitutes such as DABSO as sulfonyl sources can achieve multi-component sulfur dioxide insertion and polyfluoroaromatic coupling processes under mild conditions, which can alleviate the problems of harsh synthesis reaction conditions, cumbersome steps, poor functional group compatibility or dependence on sodium sulfinate in traditional polyfluoroaryl sulfone compounds, and achieve efficient and accurate construction of polyfluoroaryl sulfone compounds. However, to date, the three-component tandem synthesis method of polyfluoroaryl sulfone compounds has not been realized.

[0063] In some embodiments, the reaction formula for the synthesis of polyfluoroaryl substituted sulfone compounds is as follows:

[0064]

[0065] In some embodiments, the solvent includes dimethyl sulfoxide (DMSO).

[0066] Preferably, the photocatalytic reaction is initiated under the irradiation of 5W blue light LEDs.

[0067] Preferably, the synthesis method further comprises the steps of:

[0068] After the photocatalytic reaction is completed, the polyfluoroaryl substituted sulfone compounds are obtained through purification.

[0069] More preferably, after the photocatalytic reaction is completed, the reaction system is quenched with a saturated saline solution, extracted three times with ethyl acetate, the organic phases are combined, dried with anhydrous sodium sulfate, the solvent is removed with a rotary evaporator, adsorbed on silica gel, and the polyfluoroaryl substituted sulfone compound can be obtained by simple column chromatography.

[0070] In some embodiments, the polyfluoroaromatic compound has the chemical formula:

[0071]

[0072] And / or, the chemical structural formula of alkyl potassium trifluoroborate is:

[0073] R3 -BF 3 K

[0074] And / or, the photocatalyst comprises [Ir(dtbbpy)[dF(CF 3 )ppy] 2 ]PF 6 ; [Ir(dtbbpy)[dF(CF 3 )ppy] 2 ]PF 6 The chemical structure is:

[0075]

[0076] In some embodiments, the molar ratio of the polyfluoroaromatic compound, DABSO, potassium alkyl trifluoroborate and the photocatalyst is 1:(1-3):(1-3):(0.01-0.03).

[0077] More preferably, the molar ratio of the polyfluoroaromatic compound, the DABSO, the potassium alkyl trifluoroborate and the photocatalyst is 1:1:1.5:0.015. Carrying out the reaction at this molar ratio can obtain a higher yield with better atomic utilization and has atom economy.

[0078] In some embodiments, the ratio of the polyfluoroaromatic compound to the solvent is 0.2 mmol: (1-3) ml.

[0079] More preferably, the dosage ratio of the polyfluoroaromatic compound to the solvent is 0.2 mmol:2 ml. Under this dosage ratio, the concentration of the reaction system is 0.1 M, and the reaction can proceed at a better reaction rate.

[0080] In some embodiments, during the photocatalytic reaction, the reaction temperature is 18°C ​​to 40°C.

[0081] More preferably, the reaction temperature is 25°C.

[0082] In some embodiments, in the photocatalytic reaction, the reaction time is 24 hours to 96 hours.

[0083] More preferably, the reaction time is 24 h.

[0084] The invention provides application of the polyfluoroaryl substituted sulfone compounds in the medical field.

[0085] The present invention can synthesize the following polyfluoroaryl substituted sulfone compounds:

[0086]

[0087] 4ea is the corresponding ester containing menthol structure. Menthol can be used as a flavoring agent for toothpaste, perfume, beverages and candies. It is used as a stimulant in medicine, acting on the skin or mucous membrane, and has a cooling and antipruritic effect. It can be taken orally as a carminative for headaches and inflammation of the nose, pharynx and throat. The present invention can modify natural products such as menthol or active pharmaceutical molecules to synthesize polyfluoroaryl substituted sulfone compounds such as 4ea.

[0088] Example

[0089] This embodiment provides a polyfluoroaryl substituted sulfone compound. The general reaction formula and method are as follows. The reaction is carried out under the protection of a nitrogen atmosphere.

[0090]

[0091] Under nitrogen atmosphere, photocatalyst [Ir(dtbbpy)[dF(CF 3 )ppy] 2 ]PF 6 (1.5mol%), solvent dimethyl sulfoxide (DMSO, 2mL), polyfluoroaromatic compound 1 (0.2mmol), DABSO 2 (0.2mmol), potassium trifluoroborate 3 (0.3mmol), after stirring at room temperature for 24h under irradiation of 5W blue light LEDs, the reaction system was quenched with saturated saline solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed by a rotary evaporator, and adsorbed on silica gel. The polyfluoroaromatic substituted sulfone compound 4 was obtained by simple column chromatography.

[0092] By selecting different polyfluoroaromatic compounds 1, polyfluoroaryl substituted sulfone compounds were prepared by the above-mentioned synthesis method. The polyfluoroaryl substituted sulfone compounds were named as: 4aa, 4ba, 4ca, 4da, 4ab, 4ea, and the specific structural formulas are shown below:

[0093]

[0094] 1. Structural Characterization

[0095] 1. The polyfluoroaryl substituted sulfone compounds obtained in the examples were subjected to nuclear magnetic resonance detection. The results are as follows: Figure 1-Figure 18 shown.

[0096] The NMR spectrum of 4aa is as follows Figure 1-Figure 3 Shown: The yield is 99%. 1 HNMR (500MHz, CDCl 3 )δ4.04(s,3H),1.46(s,9H). 13 C NMR (151 MHz, CDCl 3) δ159.00, 145.48 (dm, J = 258.2Hz), 144.78 (dm, J = 259.7Hz), 118.46 (t, J = 14.5Hz), 118.17 (t, J = 17.0Hz), 63.37, 54.06, 22.90. 19 F NMR (565MHz, CDCl 3 )δ-130.51–-130.60(m),-136.11–-136.20(m).HRMS(ESI-TOF)(m / z):Calcdfor C 12 H 12 F 4 NaO 4 S([M+Na] + ),351.0285; found,351.0284.

[0097] The NMR spectrum of 4ba is as follows Figure 4-Figure 6 As shown, the yield was 99%. 1 H NMR (500 MHz, CDCl 3 )δ7.47(t,J=8.0Hz,2H),7.34(t,J=7.5Hz,1H),7.30–7.21(m,2H),1.48(s,9H). 13 C NMR (151 MHz, CDCl 3 )δ157.05,150.07,145.45(dm,J=262.7Hz),144.33(dm,J=258.2Hz),130.03 ,127.24,121.28,120.18(t,J=18.4Hz),117.52(t,J=14.0Hz),63.49,22.97. 19 F NMR (565MHz, CDCl 3 )δ-129.76–-130.39(m),-135.34–-135.77(m).HRMS(ESI-TOF)(m / z):Calcdfor C 17 H 14 F 4 NaO 4 S([M+Na] + )413.0441,found,413.0439.

[0098] The NMR spectrum of 4ca is as follows Figure 7-Figure 9 As shown, the yield was 63%. 1 H NMR (500 MHz, CDCl 3 )δ1.47(s,9H).13 C NMR (151 MHz, CDCl 3 )δ148.51–148.11(m),146.86–146.29(m),144.69–144.29(m),121.87(t,J=15.0Hz),106.16,63.66,22.74. 19 F NMR (565MHz, CDCl 3 )δ-128.11–-128.27(m),-128.29–-128.42(m).

[0099] The NMR spectrum of 4da is as follows Figure 10-12 As shown, the yield is 68%. 1 HNMR (500MHz, CDCl 3 )δ1.48(s,9H). 13 C NMR (151 MHz, CDCl 3 )δ144.38(dm,J=250.6Hz),140.23(dm,J=273.3Hz),128.24(t,J=13.2Hz),63.45,22.70. 19 F NMR (565MHz, CDCl 3 )δ-85.29–-86.73(m),-132.62–-132.95(m).

[0100] The NMR spectrum of 4ab is shown in Figure 13-Figure 15 As shown, the yield was 83%. 1 HNMR (500MHz, CDCl 3 )δ7.38(t,J=10.0Hz,1H),7.34(t,J=7.5Hz,2H),7.29–7.27(m,2H),4.59(s,2H),4.00(s,3H). 13 C NMR (151 MHz, CDCl 3 )δ158.70,144.43(dm,J=256.7Hz),130.66,129.82,129.17,125.83,120.15(t,J=14.7Hz),117.66(t,J=16.7Hz),63.84,53.86. 19 F NMR (565MHz, CDCl 3 )δ-134.47–-134.86(m),-135.94–-136.17(m).HRMS(ESI-TOF)(m / z):Calcd for C 15 H 10 F4 NaO 4 S([M+Na] + ),385.0128;found,385.0117.

[0101] The NMR spectrum of 4ea is as follows Figure 16-Figure 18 As shown, the yield is 99%. 1 H NMR (500 MHz, CDCl 3 )δ5.03(td,J=11.0,4.5Hz,2H),2.21–2.13(m,1H),1.97(m,1H),1.74(m,2H),1.60–1.36(m, 12H),1.20–1.04(m,2H),0.96(d,J=6.5Hz,3H),0.93(d,J=7.0Hz,3H),0.82(d,J=7.0Hz,3H). 13 C NMR (151 MHz, CDCl 3 )δ157.98,145.27(dm,J=267.2Hz),144.22(dm,J=259.7Hz),119.09(t,J=18.4Hz),117.69(t,J =14.5Hz),78.60,63.11,46.80,40.51,33.95,31.49,25.93,23.04,22.71,21.87,20.71,15.80. 19 F NMR (565MHz, CDCl 3 )δ-130.56–-130.68(m),-136.44–-137.41(m).HRMS(ESI-TOF)(m / z):Calcd for C 21 H 28 F 4 NaO 4 S([M+Na] + ),475.1537;found,475.1532.

[0102] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A polyfluoroaryl substituted sulfone compound, characterized in that: Its chemical structure is: in: OR1 includes methoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, and an alkoxy group derived from menthol, fructose diacetone, and gingerone; R2 includes one of cyano, trifluoromethyl, and ketocarbonyl; R3 includes one of tert-butyl, isopropyl, ethyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, and substituted or unsubstituted benzyl.

2. A method for synthesizing a polyfluoroaryl substituted sulfone compound, characterized in that: The method for preparing the polyfluoroaryl substituted sulfone compound according to claim 1 comprises the steps of: In an inert atmosphere, under the action of a photocatalyst, the reaction materials are irradiated with visible light in a solvent to undergo a photocatalytic reaction to prepare a polyfluoroaryl substituted sulfone compound; The reaction materials include polyfluoroaromatic compounds, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct and alkyl potassium trifluoroborate.

3. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 2, characterized in that: The chemical structural formula of the polyfluoroaromatic compound is: And / or, the chemical structural formula of the alkyl potassium trifluoroborate is: R3-BF3K And / or, the photocatalyst comprises [Ir(dtbbpy)[dF(CF3)ppy]2]PF6; the chemical structure of [Ir(dtbbpy)[dF(CF3)ppy]2]PF6 is:

4. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 2, characterized in that: The molar ratio of the polyfluoroaromatic compound, the bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, the alkyl potassium trifluoroborate and the photocatalyst is 1:(1-3):(1-3):(0.01-0.03).

5. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 2, characterized in that: The usage ratio of the polyfluoroaromatic compound and the solvent is 0.2mmol:(1-3)ml.

6. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 2, characterized in that: In the photocatalytic reaction, the reaction temperature is 18°C ​​to 40°C.

7. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 2, characterized in that: In the photocatalytic reaction, the reaction time is 24h to 96h.

8. Use of the polyfluoroaryl substituted sulfone compound according to claim 1 or the polyfluoroaryl substituted sulfone compound synthesized by the synthesis method according to any one of claims 2 to 7 in the field of medicine.

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