Synthesis method for synthesizing methylsulfonyl thioflavone derivative by photocatalysis of 2-methylthio benzyne ketone and application of methylsulfonyl thioflavone derivative

Abstract

The synthesis method comprises the following steps: adding a methylthio phenyl alkynone compound as shown in a formula (I), 2-bromo-2, 2-difluoro-N-aryl acetamide as shown in a formula (II) and DABSO as shown in a formula (III) into a reaction solvent, carrying out stirring reaction under the conditions of nitrogen protection and illumination, and carrying out filtering, washing and drying, thereby obtaining the methylsulfonyl thioflavone derivative as shown in the formula (I). The synthesis method comprises the following steps: adding a methylthio phenyl alkynone compound as shown in the formula (I), 2-bromo-2, 2-difluoro-N-aryl acetamide as shown in the formula (II) and DABSO as shown in the formula (III) into the reaction solvent; after the reaction is finished, the reaction liquid is subjected to post-treatment to obtain a target compound, namely the methylsulfonyl-containing thioflavone derivative with the anti-tumor activity, shown as a formula (IV), the reaction equation is # imgabs0, and DABSO is a bis (sulfur dioxide)-1, 4-diazabicyclo [2.2. 2] octane adduct; in the formula (I) and the formula (IV), R is selected from a bromine atom or a pyridine ring; r1 is selected from a cyano group, a halogen group or a thienyl group. The method has the advantages of simple operation process, cheap and easily available raw materials, mild reaction conditions, environmental protection, atom economy and high yield.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a synthesis method and application of a methylsulfonylthioflavone derivative synthesized by photocatalytic 2-methylthiobenzophenone. Background Art

[0002] Thioflavones are one of the most important and widely distributed active skeletons in natural products, drugs and functional materials. In the past few decades, thioflavonoids have attracted extensive attention due to their biological activities in antibacterial, antiviral and antimalarial activities. In addition, thioflavonoids and their oxidized sulfone derivatives show very promising applications in drug-related molecules and advanced materials, such as anti-infective agents and photolabile protecting groups. Nowadays, the development of new and simple synthetic methods to obtain structurally diverse thioflavonoids with applications is highly desirable.

[0003]

[0004] Compounds containing sulfonyl groups have attracted great interest due to their importance in pharmaceuticals and materials science. Among these sulfonyl compounds, methylsulfonyl-substituted skeletons are important skeletons, which are ubiquitous in commercially available drugs and bioactive molecules. Due to the "magic methyl effect" in drug discovery, significant efforts have been made to introduce methylsulfonyl groups into bioactive molecules. Traditionally, such methylsulfonyl-containing compounds are constructed by oxidation of the corresponding methyl sulfide. In recent years, alternative methods for forming methylsulfonyl-containing compounds have also been developed, including mesylation reactions using dimethyl sulfoxide as a methylsulfonyl substitute. However, harsh reaction conditions and the use of oxidants limit the application of these methods. Therefore, a mild and effective route to introduce methylsulfonyl groups into bioactive molecules is highly desirable.

[0005] For example, in 2020, Yu Chuanming et al. reported the reaction of synthesizing various 3-alkylthiochromones by radical-initiated cyclization of methylthio-substituted alkynes with the addition of excess TBPB as an oxidant. (Eur. J. Org. Chem. 2020, 4534–4541). In 2022, Wu Jie et al. also reported the reaction of preparing methylsulfonylthioflavones by free radical relay reaction of methylthiophenyl alkynone and potassium metabisulfite under photocatalytic conditions, using precious metal iridium as a catalyst and sodium methyl bisulfite as an initiator (Org. Chem. Front., 2022, 9, 450–455). However, in the prior art, it is still challenging to construct methylsulfonyl-containing thioflavones derivatives with anti-tumor activity, especially in the absence of photocatalysts. Summary of the invention

[0006] In view of the above technical problems existing in the prior art, the object of the present invention is to provide a synthesis method and application of photocatalytic 2-methylthiophenyl phenanthene ketone to prepare methylsulfonylthioflavone derivatives with anti-tumor activity, which has simple operation, mild reaction conditions, high product purity and green method.

[0007] In order to achieve the above object, the present invention proposes the following technical solutions:

[0008] A synthesis method for preparing a methylsulfonylthioflavone derivative with anti-tumor activity by photocatalytic 2-methylthiophenyl alkynone, comprising: adding a methylthiophenyl alkynone compound shown in formula (I), 2-bromo-2,2-difluoro-N-arylacetamide shown in formula (II), and DABSO shown in formula (III) to a reaction solvent, protecting with nitrogen, stirring and reacting under light conditions, and after the reaction is completed, the reaction solution is post-treated to obtain a target compound of formula (IV) containing a methylsulfonylthioflavone derivative, and the reaction equation is as follows:

[0009]

[0010] The DABSO is bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct;

[0011] In formula (I) and formula (IV), R is selected from a bromine atom or a pyridine ring; R 1 is selected from a cyano group, a halogen group or a thienyl group.

[0012] Furthermore, the reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile and 1,2-dichloroethane, preferably 1,2-dichloroethane. The concentration of the methylthiophenyl alkynyl ketone compound represented by formula (I) in the reaction solvent is 0.02-0.2 mol / L.

[0013] Furthermore, the light source of the illumination is blue light, white light or purple light, preferably blue light.

[0014] Furthermore, the reaction temperature is 20 to 35°C, preferably 25 to 30°C.

[0015] Furthermore, the reaction time is 16 to 30 hours, preferably 18 to 20 hours.

[0016] Furthermore, the molar ratio of the methylthiophenyl alkynyl ketone compound represented by formula (I), the 2-bromo-2,2-difluoro-N-phenylacetamide represented by formula (II), and the DABSO represented by formula (III) is 1:0.1~0.5:1.0~2.0, and the preferred molar ratio is 1:0.2:1.5.

[0017] Furthermore, the reaction solution is post-treated as follows: the reaction solution is quenched with a saturated sodium bicarbonate solution, washed with saturated saline, extracted with ethyl acetate, the organic layers are combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which is separated and purified by a chromatographic column to obtain a mesylthioflavone derivative represented by the target compound formula (IV). The eluent for separation and purification by the chromatographic column is a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 3 to 5:1.

[0018] Furthermore, a methylthiophenyl alkynyl ketone compound represented by formula (I), 2-bromo-2,2-difluoro-N-phenylacetamide represented by formula (II), DABSO represented by formula (III) and a reaction solvent are added to a reaction tube equipped with a magnetic stirrer. After nitrogen replacement three times, the reaction system is placed under light source irradiation and stirred at 20-35° C. for reaction. After the reaction is completed, the reaction solution is quenched with saturated sodium bicarbonate, washed with saturated brine, and the mixture obtained after washing is extracted with ethyl acetate. After the organic layers are combined, they are dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by a chromatographic column to obtain a target compound represented by formula (IV) which is a methylsulfonylthioflavone derivative with anti-tumor activity.

[0019] The mesylthioflavone derivatives described in the present application are used to prepare inhibitors for inhibiting MCF-7 or 4T1 tumor cells.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] 1) The present invention can realize the synthesis of mesylthioflavone derivatives with anti-tumor activity only by light source irradiation conditions, without adding any photocatalyst, using 2-bromo-2,2-difluoro-N-phenylacetamide as the initiator of the reaction, avoiding the use of oxidants, transition metal catalysts and specific ligands in conventional technologies, and effectively controlling the cost of the reaction;

[0022] 2) The present invention adopts a one-step synthesis method to prepare the target compound. Compared with conventional techniques, this method is simple to operate and does not require pre-functionalization of the reaction substrate;

[0023] 3) Compared with conventional technologies, the present invention has higher atom economy;

[0024] 4) The present invention has the advantages of simple operation, mild reaction conditions, simple post-treatment, and anti-tumor activity, which conforms to the development concept of green chemistry and is suitable for industrial promotion and application. DETAILED DESCRIPTION

[0025] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0026] Example 12-(4-Chlorophenyl)-3-(methylsulfonyl)-4H-thiochromen-4-one

[0027]

[0028] Compound (I) 3-(4-chlorophenyl)-1-(2-(methylthio)phenyl)prop-2-yn-1-one (57.2 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W, and the reaction was stirred at 25° C. for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 73% and an HPLC purity of 98.7%.

[0029] Example 22-(4-Chlorophenyl)-3-(methylsulfonyl)-4H-thiochromen-4-one

[0030]

[0031] Compound (I) 3-(4-chlorophenyl)-1-(2-(methylthio)phenyl)prop-2-yn-1-one (57.2 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. Acetonitrile (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W and stirred at 25° C. for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 53% and an HPLC purity of 98.7%. The comparison of solvents shows that 1,2-dichloroethane is more conducive to the reaction than acetonitrile.

[0032] 1HNMR(400MHz,DMSO-d6)δ8.4(dd,J=8.1,1.4Hz,1H),8.0(dd,J=8.2,1.2Hz,1H),7.9(dd d,J=8.2,7.1,1.5Hz,1H),7.8(ddd,J=8.2,7.1,1.3Hz,1H),7.6–7.5(m,4H),3.4(s,3H).

[0033] 13 CNMR(101MHz,DMSO)δ176.5,160.3,135.3,134.9,133.6,133.3,132.4,130.9,130.0,129.3,128.2,128.0,126.2,44.7.

[0034] Example 32-(4-Fluorophenyl)-3-(methylsulfonyl)-4H-thiochromen-4-one

[0035]

[0036] Compound (I) 3-(4-fluorophenyl)-1-(2-(methylthio)phenyl)prop-2-yn-1-one (54.0 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W, and the reaction was stirred at 25° C. for 18 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 78% and an HPLC purity of 98.6%.

[0037] 1 HNMR(400MHz, DMSO-d6)δ8.4(dd,J=8.2,1.4Hz,1H),7.9(dd,J=8.1,1.2Hz,1H),7.9–7.8(m, 1H),7.8(td,J=7.6,1.3Hz,1H),7.6(dd,J=8.6,5.5Hz,2H),7.3(t,J=8.9Hz,2H),3.4(s,3H).

[0038] 13CNMR(101MHz,DMSO)δ176.6,163.1(d,J=247.6Hz),160.5,135.4,133.3,132.5,131.0(d ,J=3.3Hz),131.0,130.7(d,J=8.9Hz),129.3,128.2,126.2,115.1(d,J=22.3Hz),44.7.

[0039] Example 42-(4-Bromophenyl)-3-(methylsulfonyl)-4H-thiochromen-4-one

[0040]

[0041] Compound (I) 3-(4-bromophenyl)-1-(2-(methylthio)phenyl)prop-2-yn-1-one (66.0 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen substitution three times, the reaction system was irradiated with a blue light with a power of 25 W and stirred at 25° C. for 18 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 70% and an HPLC purity of 98.7%.

[0042] 1 HNMR (400MHz, DMSO-d6) δ8.4 (dd, J=8.2, 1.4Hz, 11H), 8.0 (dd, J=8.1, 1.2Hz, 1H), 7.9 (td, J=8.1, 7.6 ,1.5Hz,1H),7.8(ddd,J=8.2,7.1,1.3Hz,1H),7.7(d,J=8.5Hz,2H),7.5(d,J=8.4Hz,2H),3.4(s,3H).

[0043] 13 CNMR(101MHz,DMSO)δ176.5,160.3,135.3,134.0,133.3,132.3,130.9,130.9,130.2,129.3,128.2,126.2,123.7,44.7.

[0044] Example 54-(3-(Methylsulfonyl)-4-oxo-4H-thiochromen-2-yl)benzonitrile

[0045]

[0046] Compound (I) 4-(3-(2-(methylthio)phenyl)-3-oxoprop-1-yn-1-yl)benzonitrile (55.4 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W and stirred at 30° C. for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 3:1 to obtain the target product with a yield of 63% and an HPLC purity of 98.8%. 1 HNMR (400MHz, DMSO-d6) δ8.4(dd,J=8.2,1.5Hz,1H),8.0(d,J=8.4Hz,3H),7.9(td,J=8.2,7.7,1.5Hz,1H),7.8(d,J=8.5Hz,3H),3.4(s,3H).

[0047] 13 CNMR(101MHz,DMSO)δ176.3,159.6,139.4,135.1,133.4,132.3,131.8,130.9,129.5,129.1,128.2,126.3,118.3,112.5,44.6.

[0048] Example 6 Methyl 4-(3-(methylsulfonyl)-4-oxo-4H-thiochromen-2-yl)benzoate

[0049]

[0050] Compound (I) methyl 4-(3-(2-(methylthio)phenyl)-3-oxoprop-1-yn-1-yl)benzoate (55.4 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W and stirred at 20° C. for 20 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 5:1 to obtain the target product with a yield of 58% and an HPLC purity of 98.5%. 1 HNMR (400MHz, DMSO-d6) δ8.4(d,J=8.1Hz,1H),8.0(d,J=8.4Hz,2H),8.0(d,J=8.1Hz,1 H),7.9(t,J=7.6Hz,1H),7.8–7.7(m,1H),7.7(d,J=8.3Hz,2H),3.9(s,3H),3.4(s,3H).

[0051] 13 CNMR(101MHz,DMSO)δ176.4,165.7,160.3,139.3,135.2,133.3,132.3,130.9,130.7,129.4,128.6,128.5,128.2,126.3,52.4,44.6.

[0052] Example 7 2-(3-Bromophenyl)-3-(methylsulfonyl)-4H-thiochromen-4-one

[0053]

[0054] Compound (I) 3-(3-bromophenyl)-1-(2-(methylthio)phenyl)prop-2-yn-1-one (66.0 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W and stirred at 25° C. for 20 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 68% and an HPLC purity of 98.4%.

[0055] 1 HNMR(400MHz, DMSO-d6)δ8.4(dd,J=8.1,1.5Hz,1H),7.9(dd,J=8.1,1.2Hz,1H),7.9–7.8(m,1H),7.8(t,J=1 .9Hz,1H),7.7(ddd,J=17.7,8.2,1.5Hz,2H),7.6(dt,J=7.8,1.3Hz,1H),7.4(t,J=7.9Hz,11H),3.4(s,3H).

[0056] 13 CNMR(101MHz,DMSO)δ176.4,159.6,136.8,135.3,133.3,132.7,132.3,130.9,130.4,130.0,129.3,128.2,127.3,126.2,120.9,44.7.

[0057] Example 87-Bromo-3-(methylsulfonyl)-2-phenyl-4H-thiochromen-4-one

[0058]

[0059] Compound (I) 1-(4-bromo-2-(methylthio)phenyl)-3-phenylprop-2-yn-1-one (66.0 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (11.6 mg, 0.04 mmol), and compound (III) DABSO (72.1 mg, 0.3 mmol) were added to a reaction mixture equipped with a magnetic stirrer. 1,2-dichloroethane (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with a blue light with a power of 25 W and stirred at 25° C. for 20 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 63% and an HPLC purity of 98.9%.

[0060] 1 HNMR (400MHz, DMSO-d6) δ8.3(d,J=1.9Hz,1H),8.3(d,J=8.7Hz,1H),7.9(dd,J=8.6,2.0Hz,1H),7.6–7.5(m,3H),7.5–7.5(m,2H),3.4(s,3H).

[0061] 13 CNMR(101MHz,DMSO)δ176.2,161.6,137.3,134.5,132.4,132.3,130.2,130.2,130.0,128.4,128.2,128.0,127.4,44.7.

[0062] Example 92-(4-methoxyphenyl)-3-(methylsulfonyl)-4H-thiopyrano[2,3-b]pyridin-4-one

[0063]

[0064] Compound (I) 3-(4-methoxyphenyl)-1-(2-(methylthio)pyridin-3-yl)prop-2-yn-1-one (56.6 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (23.1 mg, 0.08 mmol), and compound (III) DABSO (96.1 mg, 0.4 mmol) were added to a reaction mixture equipped with a magnetic stirrer. Acetonitrile (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated under purple light with a power of 25 W and stirred at 35° C. for 25 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 60% and an HPLC purity of 98.7%.

[0065] 1 HNMR (400MHz, DMSO-d6) δ9.0 (dd, J=4.6, 1.8Hz, 11H), 8.7 (dd, J=8.2, 1.8Hz, 1H), 7.8 (dd ,J=8.1,4.6Hz,11H),7.5(d,J=8.3Hz,2H),7.1(d,J=8.4Hz,2H),3.8(s,3H),3.4(s,3H).

[0066] 13 CNMR(101MHz,DMSO)δ177.6,162.3,161.1,155.8,154.1,136.9,132.8,130.0,128.3,126.4,124.4,113.5,55.3,44.6.

[0067] Example 103-(Methylsulfonyl)-2-(thiophen-3-yl)-4H-thiochromen-4-one

[0068]

[0069] Compound (I) 1-(2-(methylthio)phenyl)-3-(thiophen-3-yl)prop-2-yn-1-one (51.6 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (28.9 mg, 0.1 mmol), and compound (III) DABSO (96.1 mg, 0.4 mmol) were added to a reaction mixture equipped with a magnetic stirrer. Tetrahydrofuran (2.0 mL) was added to the mixture. After nitrogen replacement three times, the reaction system was irradiated with white light at a power of 25 W and stirred at 35° C. for 30 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl, separated into layers, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate in a volume ratio of 4:1 to obtain the target product with a yield of 48% and an HPLC purity of 98.2%.

[0070] 1 HNMR(400MHz,DMSO-d6)δ8.4(dd,J=8.2,1.4Hz,1H),8.0(dd,J=3.0,1.3Hz,1H),7.9(dd,J=8.1,1.2Hz,1H),7.9– 7.8(m,1H),7.7(ddd,J=8.3,7.1,1.3Hz,1H),7.7(dd,J=5.0,3.0Hz,1H),7.4(dd,J=5.0,1.3Hz,1H),3.4(s,3H).

[0071] 13 CNMR(101MHz,DMSO)δ176.8,156.0,135.4,134.1,133.1,132.2,131.1,129.1,128.8,128.2,127.7,126.3,126.0,44.7.

[0072] Example 11 Antitumor Activity Test:

[0073] The effects of the compounds on the proliferation of MCF-7 and 4T1 cells are analyzed below:

[0074] The cell survival rate was determined by MTT method. MCF-7 cells: inoculated in DMEM medium containing 10% FBS, 1% penicillin-streptomycin mixed solution, and cultured in a 37°C constant temperature incubator containing 5% CO2. 4T1 cells: 87% RPMI1640 medium, 10% serum, 1% Glutamax, 1% Sodium Pyruvate 100mMSolution, 1% Non-essential Amino Acids, cultured in a 37°C constant temperature incubator containing 5% CO2.

[0075] MCF-7 cells and 4T1 cells in the logarithmic growth phase were inoculated into 96-well plates (100 μL, 8 × 10 4 / mL), incubated at 37°C in a 5% CO2 incubator for 24h. Subsequently, the two cells were treated with different compounds at a concentration of 20μM for 48 hours each (three parallel groups were set for each concentration), and the experimental group without drug addition was used as a blank control. Subsequently, 10μL of 5mg / mL MTT solution was added to each well, incubated at 37°C in a 5% CO2 incubator for 4 hours, the supernatant was discarded, 100μLDMSO was added to each well, and after shaking at 500rpm for 10min, the absorbance at a wavelength of 492nm was measured. The detection formula for cell survival rate is:

[0076] Cell survival rate (%) = average OD of drug-treated group / average OD of control group × 100%.

[0077] Experimental results: Compared with the blank control group, the proliferation changes of MCF-7 and 4T1 cells in the experimental groups treated with different compounds for 48 hours are shown in the table:

[0078] The test results are shown in Table 1.

[0079] Table 1 Antitumor activity of compounds IV-b to IV-d, IV-F, and IV-h at a concentration of 20 μM

[0080]

[0081] Note: Hydroxyflavone (20 μM) is the control drug, metformin (2.5 mM) is the control drug, and CK is the blank control.

[0082] The anti-tumor activity test results in Table 1 show that at a concentration of 20 μM, the methylsulfonyl-containing thioflavonoid derivatives IV-b to IV-d, IV-F, and IV-h of the present invention all exhibited certain inhibitory activity against the test targets, among which compounds IV-b and IV-c exhibited good inhibitory activity against tumor cells MCF-7 and 4T1.

[0083] The contents described in this specification are merely an enumeration of implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as being limited to the specific forms described in the embodiments.

Claims

1. A method for synthesizing methylsulfonylthioflavone derivatives by photocatalytic 2-methylthioation of phenylacetin, characterized in that A methylthiophenyl alkynone compound represented by formula (I), 2-bromo-2,2-difluoro-N-arylacetamide represented by formula (II), and DABSO represented by formula (III) are added to a reaction solvent, and the mixture is stirred under nitrogen protection and light conditions for reaction. After the reaction is completed, the reaction solution is post-treated to obtain a target compound represented by formula (IV) containing a methylsulfonylthioflavonoid derivative, and the reaction equation is as follows: The DABSO is bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct; In formula (I) and formula (IV), R is selected from a bromine atom or a pyridine ring; R 1 is selected from a cyano group, a halogen group or a thienyl group.

2. The method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 1, characterized in that The reaction solvent is selected from one or more of tetrahydrofuran, acetonitrile and 1,2-dichloroethane, preferably 1,2-dichloroethane, and the concentration of the methylthiophenyl alkynyl ketone compound represented by formula (I) in the reaction solvent is 0.02-0.2 mol / L.

3. The method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 1, characterized in that The light source of the illumination is blue light, white light or purple light, preferably blue light.

4. The method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 1, characterized in that The reaction temperature is 20 to 35°C, preferably 25 to 30°C.

5. The method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 1, characterized in that The reaction time is 16 to 30 hours, preferably 18 to 20 hours.

6. The method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 1, characterized in that The molar ratio of the methylthiophenyl alkynone compound represented by formula (I), the 2-bromo-2,2-difluoro-N-phenylacetamide represented by formula (II), and the DABSO represented by formula (III) is 1:0.1-0.5:1.0-2.0, and the preferred molar ratio is 1:0.2:1.

5.

7. The method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 1, characterized in that The post-treatment process of the reaction solution is as follows: the reaction solution is quenched with a saturated sodium bicarbonate solution, washed with saturated brine, extracted with ethyl acetate, the organic layers are combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, and the crude product is separated and purified by a chromatographic column to obtain the target compound methylsulfonylthioflavone derivative represented by formula (IV).

8. A method for synthesizing a methylsulfonylthioflavone derivative by photocatalytic 2-methylthiobenzophenone as claimed in claim 7, characterized in that The eluent for separation and purification by the chromatographic column is a mixed solvent of petroleum ether / ethyl acetate in a volume ratio of 3 to 5:

1.

9. A mesylthioflavone derivative synthesized according to the method of any one of claims 1 to 8.

10. The use of the mesylthioflavone derivative according to claim 9, characterized in that The mesylthioflavone derivative is used for preparing an inhibitor for inhibiting MCF-7 or 4T1 tumor cells.

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