Method for photocatalytic three-component preparation of coumarin derivatives and application thereof

Abstract

The application discloses a method for preparing coumarin derivatives by photocatalysis of three components and application, which comprises the following steps: adding propynoate compounds shown in formula (I), 2-bromo-2,2-difluoro-N-aryl / alkyl acetamides shown in formula (II) and DABSO shown in formula (III) into a reaction solvent, stirring and reacting under the protection of nitrogen and light, and obtaining target compounds, i.e., difluoroaminosulfonylated / bicyclic coumarin derivatives shown in formula (IV) with antitumor activity after post-treatment of the reaction liquid, wherein the reaction equation is as follows: the DABSO is bis(dioxidosulfur)-1,4-diazabicyclo[2.2.2]octane adduct; R is selected from H, C1-C4 alkyl, a halogen group, methoxy or trifluoromethyl; R 1 is selected from C1-C6 alkyl or aryl; and R 2 is selected from aryl or C1-C6 alkyl. The application has the advantages of simple operation, cheap and easily available raw materials, mild reaction conditions, green environmental protection, high atom economy and yield, and difluoroaminosulfonylated coumarin derivatives with antitumor activity.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method and application of photocatalytic three-component preparation of coumarin derivatives. Background Technology

[0002] Coumarins (benzopyran-2-ones, or chromone-2-ones) are an important class of oxygen-containing heterocyclic compounds with pyranone lead structures, possessing high bioavailability and low toxicity. Based on their excellent pharmacological activities, some coumarin derivatives have been approved for clinical use. On the one hand, coumarin derivatives can be used as additives in cosmetics and food, fragrances and flavorings, and agrochemicals; on the other hand, they also possess various biological activities, such as antitumor, antioxidant, antifungal, and anti-HIV effects. Therefore, the development of direct and effective synthetic methods for coumarin lead structures with potential pharmacological activity has attracted widespread attention.

[0003]

[0004] On the other hand, γ-lactam motifs also possess numerous biological activities, including antimalarial, anti-inflammatory, and antiviral activities. Surprisingly, many biological activities have also been found in difluorinated γ-lactams, suggesting that the introduction of fluorine improves the lipophilicity and metabolic stability of the active molecules. Therefore, the synthesis of 3,3-difluoro-γ-lactams has been a hot topic in synthetic organic chemistry. Current strategies focus on using N-allylbromodifluoroacetamide as a bicomponent bifunctional synthon to obtain 3,3-difluoro-γ-lactam derivatives under metal-catalyzed and photocatalytic conditions. For example, in 2021, Jin et al. reported a cascade monocyclization reaction of N-allylbromodifluoroacetamide with 2-aminonaphthoquinone under photocatalytic conditions with the addition of amine additives (Org. Lett. 2021, 23, 1862-1867). In 2021, Jin et al. also reported the self-cyclization reaction of N-allyl bromide difluoroacetamide under photocatalytic conditions, using fluorescein as a photocatalyst and adding amine additives (Org. Chem. Front., 2021, 8, 736–742). Compared with the above work, especially in the absence of a photocatalyst, generating sulfonated coumarin compounds with antitumor activity remains challenging and has been rarely studied. Based on our previous work on radical cyclization, we here invented a photocatalyst-free three-component difluoroaminosulfonation reaction of visible light-induced propynyl ester and N-allyl bromide difluoroacetamide with sulfur dioxide to construct difluoroaminosulfonated / bicyclized coumarin compounds with antitumor activity. Summary of the Invention

[0005] In view of the above-mentioned technical problems existing in the prior art, the purpose of the present invention is to provide a photocatalytic synthesis method for preparing coumarin derivatives with anti-tumor activity that is simple to operate, has mild reaction conditions, produces high-purity products, and is green.

[0006] To achieve the above objectives, the present invention proposes the following technical solution:

[0007] A photocatalytic three-component method for preparing coumarin derivatives includes: adding a propynyl ester compound of formula (I), a 2-bromo-2,2-difluoro-N-aryl / alkylacetamide compound of formula (II), and DABSO of formula (III) to a reaction solvent; under nitrogen protection; stirring under light irradiation; and after the reaction is completed, post-treatment of the reaction solution yields the difluoroaminosulfonyl / bicyclized coumarin derivative of formula (IV) with antitumor activity. The reaction equation is as follows:

[0008]

[0009] The DABSO is a bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct;

[0010] In formulas (I) and (IV), R is selected from H, C1-C4 alkyl, halogen group, methoxy or trifluoromethyl; 1 Selected from C1-C6 alkyl or aryl; in formulas (II) and (IV), R 2 It is selected from aryl or C1-C6 alkyl. The aryl group can be benzyloxy, naphthyl, phenyl or substituted phenyl, and the substituent of the substituted phenyl group is one or two of halogen, C1-C4 alkyl or methoxy.

[0011] Furthermore, the reaction solvent is selected from dimethyl sulfoxide and / or acetonitrile, preferably acetonitrile.

[0012] Furthermore, the light source is blue light, white light, or violet light, preferably blue light.

[0013] Furthermore, the reaction temperature is 20–35°C, preferably 25–30°C.

[0014] Furthermore, the reaction time is 10–18 h, preferably 12–13 h.

[0015] Furthermore, the molar ratio of the propynyl ester compound shown in formula (I), the 2-bromo-2,2-difluoro-N-aryl / alkylacetamide compound shown in formula (II), and the DABSO shown in formula (III) is 1:1.5 to 3.0:1.5 to 3.0, preferably 1:2:2.

[0016] Further, the reaction solution underwent post-treatment as follows: the reaction solution was quenched with saturated sodium bicarbonate solution, washed with saturated brine, extracted with ethyl acetate, and the combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography to obtain the target compound. The eluent for column chromatography purification was a mixture of petroleum ether and ethyl acetate at a volume ratio of 6–10:1.

[0017] Further, propynate compounds of formula (I), 2-bromo-2,2-difluoro-N-aryl / alkylacetamide compounds of formula (II), DABSO of formula (III), and reaction medium were added to a reaction tube equipped with a magnetic stirrer. After nitrogen purging three times, the reaction system was placed under light source irradiation and stirred at 20-35°C. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate, washed with saturated brine, and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried with anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the difluoroaminosulfonyl / bicyclized coumarin compound of formula (IV) with antitumor activity.

[0018] This application also discloses the application of the coumarin derivatives, which are used to prepare inhibitors that inhibit MCF-7 or 4T1 tumor cells.

[0019] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0020] 1) This invention can synthesize difluoroaminosulfonyl / bicyclized coumarin compounds with antitumor activity using only light source irradiation conditions, without the need to add any photocatalyst, thus avoiding the use of oxidants, transition metal catalysts and specific ligands in conventional technologies, and effectively controlling the cost of the reaction.

[0021] 2) This invention uses a one-step synthesis method to prepare the target compound. Compared with conventional techniques, this method is simple to operate and does not require prefunctionalization of the reaction substrate.

[0022] 3) Compared with conventional technologies, this invention has higher atom economy;

[0023] 4) This invention has the advantages of simple operation, mild reaction conditions, simple post-processing, and anti-tumor activity, which are in line with the development concept of green chemistry and are suitable for industrial promotion and application. Detailed Implementation

[0024] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0025] Example 1 3,3-Difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)-1-phenylpyrrolidone-2-one

[0026]

[0027] Compound (I) phenyl-3-phenylpropionate (44.4 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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, and after purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 6:1 to obtain the target product with a yield of 90% and an HPLC purity of 98.5%.

[0028] 1 H NMR (400MHz, DMSO-d6) δ7.8(t,J=7.0Hz,1H),7.6(d,J=7.7Hz,3H),7.6–7.4(m,5H),7.4–7.3(m,3H),7.3(t,J=7.4 Hz,1H),6.9(d,J=8.2Hz,1H),4.2(dd,J=14.6,4.2Hz,1H),3.9(t,J=8.4Hz,1H),3.9–3.8(m,2H),3.7–3.5(m,1H).

[0029] 13 C NMR (101MHz, DMSO) δ 160.6 (t, J C-F =30.3Hz),160.5,156.5,153.2,137.5,135.2,132.2,129.3,129.1,128.9, 128.0,127.8,127.6,127.0,126.2,125.2,123.2,120.2,120.2,117.1(t,J C-F =256.5Hz), 116.7, 50.7 (d, J) C-F =6.0Hz), 47.6(d,J C-F =6.0Hz), 33.6(t,J C-F =21.2Hz).

[0030] 19 F NMR (376MHz, DMSO-d6) δ-108.3 (d, J=261.8Hz, 1F), -112.8 (d, J=261.8Hz, 1F).

[0031] Example 2 3,3-Difluoro-4-((7-methyl-2-oxo-4-phenyl-2H-chromene-3-yl)sulfonyl)methyl)-1-phenylpyrrolidone-2-one

[0032]

[0033] Compound (I) p-Tolyl-3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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, and after purging with nitrogen three times, the reaction system was irradiated under a blue light with a power of 25 W and stirred at 30 °C for 10 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 7:1 to obtain the target product with a yield of 87% and an HPLC purity of 98.6%.

[0034] 1 H NMR (400MHz, DMSO-d6) δ7.6(d,J=8.1Hz,2H),7.5–7.4(m,6H),7.3(d,J=6.7Hz,2H),7.3(t,J=7.5Hz,1H),7.2(d,J=8.4Hz ,1H),6.8(d,J=8.3Hz,1H),4.2(dd,J=14.5,3.9Hz,1H),3.9(ddd,J=29.6,21.5,12.3Hz,3H),3.7–3.4(m,1H),2.4(s,3H).

[0035] 13 C NMR(101MHz,DMSO)δ160.6,160.6(t,J C-F =31.3Hz),156.7,153.3,147.0,137.6,132.3,129.1,129.1,128.8,128 .0,127.8,127.6,127.0,126.4,126.2,121.9,120.2,117.8,117.2(t,J C-F=252.5Hz), 116.6, 50.6 (d, J) C-F =7.0Hz), 47.6(d,J C-F =6.0Hz), 33.6(t,J C-F =20.2Hz), 21.3.

[0036] 19 F NMR (376MHz, DMSO-d6) δ-108.3 (d, J = 261.9Hz, 1F), -112.8 (d, J = 261.8Hz, 1F).

[0037] Example 3 4-((7-(tert-butyl)-2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)-3,3-difluoro-1-phenylpyrrolidone-2-one

[0038]

[0039] Compound (Ⅰ) 4-(tert-butyl)phenyl-3-phenylpropionate (55.6 mg, 0.2 mmol), compound (Ⅱ) 2-bromo-2,2-difluoro-N-phenylacetamide (86.7 mg, 0.3 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, and after purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 13 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 7:1 to obtain the target product with a yield of 78% and an HPLC purity of 98.7%.

[0040] 1 H NMR (400MHz, DMSO-d6) δ7.6(d,J=8.5Hz,3H),7.5–7.4(m,6H),7.4(d,J=7.6Hz,2H),7.3(t,J=7.4Hz,1H),6.8( d,J=8.5Hz,1H),4.2(dd,J=14.6,4.0Hz,1H),3.8(ddd,J=34.4,14.9,9.3Hz,3H),3.7–3.4(m,1H),1.3(s,9H).

[0041] 13 C NMR(101MHz,DMSO)δ160.6,160.6(t,J C-F=30.3Hz),159.6,156.7,153.3,137.6,132.4,129.1,129.0,128.8,128 .0,127.8,127.6,126.9,126.1,122.8,122.0,120.2,117.8,117.1(t,J C-F =253.5Hz), 113.4, 50.5(d,J) C-F =7.0Hz), 47.6(d,J C-F =6.0Hz), 35.3, 33.7(t,J) C-F =21.2Hz), 30.5.

[0042] 19 FNMR(376MHz, DMSO-d6)δ-108.4(d,J=261.7Hz,1F),-112.9(d,J=261.8Hz,1F).

[0043] Example 4 3,3-Difluoro-4-(((2-oxo-4-phenyl-7-(trifluoromethyl)-2H-chromen-3-yl)sulfonyl)methyl)-1-phenylpyrrolidone-2-one

[0044]

[0045] Compound (Ⅰ) 4-(trifluoromethyl)phenyl-3-phenylpropionate (58.0 mg, 0.2 mmol), compound (Ⅱ) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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, and after purging with nitrogen three times, the reaction system was irradiated under a white light with a power of 25 W and stirred at 30 °C for 15 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 6:1 to obtain the target product with a yield of 56% and an HPLC purity of 98.8%.

[0046] 1H NMR (400MHz, DMSO-d6) δ8.1(s,1H),7.7(d,J=8.6Hz,1H),7.6(d,J=8.1Hz,2H),7.6–7.4(m,5H),7.4(d,J=7.7Hz ,2H),7.3(t,J=7.5Hz,1H),7.1(d,J=8.4Hz,1H),4.2(dd,J=14.7,4.1Hz,1H),4.0–3.8(m,3H),3.7–3.5(m,1H).

[0047] 13 C NMR (101MHz, DMSO) δ 160.6 (t, J C-F =29.3Hz),159.2,156.1,153.0,137.5,133.8(q,J C-F =33.3Hz),131.7,130.7,129.2,129.1,128.1,128.0,127.9,127.1,126.2,125.4,124.4,123.6,121.4,120.2,117.1(t,J C-F =241.5Hz), 114.2, 50.7(d,J) C-F =7.0Hz), 47.5(d,J C-F =6.0Hz), 33.5(t,J C-F =20.2Hz).

[0048] 19 F NMR (376MHz, DMSO-d6) δ-61.6 (s, 3F), -108.2 (d, J = 262.2Hz, 1F), -112.8 (d, J = 261.9Hz, 1F).

[0049] Example 5 4-((7-chloro-2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)-3,3-difluoro-1-phenylpyrrolidone-2-one

[0050]

[0051] Compound (I) p-chlorophenyl 3-phenylpropionate (51.2 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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, and after purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 6:1 to obtain the target product with a yield of 65% and an HPLC purity of 98.5%.

[0052] 1 H NMR(400MHz, DMSO-d6)δ7.9(s,1H),7.6(d,J=8.1Hz,2H),7.6–7.4(m,6H),7.4(s,2H),7.3(t,J=7.5Hz,1H ),6.9(d,J=8.7Hz,1H),4.2(dd,J=14.5,4.1Hz,1H),3.9(ddd,J=23.0,14.9,9.6Hz,3H),3.7–3.4(m,1H).

[0053] 13 C NMR (101MHz, DMSO) δ 160.6 (t, J C-F =31.3Hz),159.9,156.2,153.5,139.6,137.5,131.9,130.7,129.1,129.0, 128.0,127.9,127.8,127.0,126.2,125.6,123.3,120.2,119.4,117.1(t,J C-F =256.5Hz), 116.8, 50.7 (d, J) C-F =6.0Hz), 47.6(d,J C-F =6.0Hz), 33.5(t,J C-F =20.2Hz).

[0054] 19 F NMR (376MHz, DMSO-d6) δ-108.2 (d, J = 262.0Hz, 1F), -112.8 (d, J = 261.8Hz, 1F).

[0055] Example 6 3,3-Difluoro-4-(((4-(4-fluorophenyl)-2-oxo-2H-chromene-3-yl)sulfonyl)methyl)-1-phenylpyrrolidone-2-one

[0056]

[0057] Compound (Ⅰ) 3-(4-fluorophenyl)propynyl ester (48.0 mg, 0.2 mmol), compound (Ⅱ) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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 purging with nitrogen three times, the reaction system was irradiated under ultraviolet light at a power of 25 W and stirred at 30 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 7:1 to obtain the target product with a yield of 53% and an HPLC purity of 98.4%.

[0058] 1 H NMR (400MHz, DMSO-d6) δ7.8(t,J=7.9Hz,1H),7.6(d,J=8.1Hz,3H),7.5–7.2(m,8H),7.0(d,J= 8.1Hz,1H),4.2(dd,J=14.6,4.1Hz,1H),3.9(ddd,J=21.4,17.2,9.9Hz,3H),3.7–3.4(m,1H).

[0059] 13 C NMR(101MHz,DMSO)δ163.6,161.2,160.6(t,J C-F =30.2Hz),159.8,156.5,153.2,137.6,135.3,130.4(d,J C-F =8.6Hz), 129.5(d,J C-F =8.3Hz),129.4,129.3,129.1,128.4(d,J C-F =3.2Hz),126.2,125.3,123.6,120.2,120.2,117.2(t,J C-F =249.5Hz), 116.7, 115.0 (dd, J C-F =22.0,11.9Hz),50.6(d,J) C-F=7.0Hz), 47.6(d,J C-F =6.3Hz), 33.5(t,J C-F =21.2Hz). 19 F NMR(376MHz, DMSO-d6)δ-108.1(d,J=262.0Hz,1F),-112.7(d,J=261.7Hz,1F),-112.8(s,1F).

[0060] Example 7 3,3-Difluoro-4-(((2-oxo-4-(p-tolyl)-2H-chromen-3-yl)sulfonyl)methyl)-1-phenylpyrrolidone-2-one

[0061]

[0062] Compound (I) phenyl 3-(4-methylphenyl)propynate (47.2 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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, and after purging with nitrogen three times, the reaction system was irradiated under ultraviolet light at a power of 25 W and stirred at 30 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 8:1 to obtain the target product with a yield of 40% and an HPLC purity of 98.9%.

[0063] 1 H NMR (400MHz, DMSO-d6) δ7.6(d,J=8.0Hz,2H),7.5(dd,J=15.6,6.7Hz,6H),7.3(d,J=6.7Hz,2H),7.3(t,J=7.5Hz,1H),7.2(d,J=8.4Hz,1H), 6.8(d,J=8.2Hz,1H), 4.2(dd,J=14.6,4.1Hz,1H), 3.9(t,J=9.4Hz,1H), 3.8(dd,J=14.4,9.0Hz,1H), 3.8(d,J=10.3Hz,1H), 3.6–3.4(m,1H).

[0064] 13C NMR (101MHz, DMSO) δ161.4,161.1,157.2,153.8,147.5,138.1,132.8,129.6,129.6,129.3,128.3(t,J C-F =19.2Hz),127.5,126.9,126.7,122.4,120.7,118.3,117.7(t,J C-F =246.4Hz), 117.1, 51.0(d,J) C-F =7.0Hz), 48.1(d,J C-F =6.3Hz), 34.1(t,J C-F =20.2Hz), 21.8.

[0065] 19 F NMR (376MHz, DMSO-d6) δ-108.3 (d, J = 261.6Hz, 1F), -112.8 (d, J = 261.9Hz, 1F).

[0066] Example 8 1-(4-bromophenyl)-3,3-difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidone-2-one

[0067]

[0068] Compounds (I) phenyl-3-phenylpropionate (44.4 mg, 0.2 mmol), (II) N-allyl-2-bromo-N-(4-bromophenyl)-2,2-difluoroacetamide (146.8 mg, 0.4 mmol), and (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, and after purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 7:1 to obtain the target product with a yield of 78% and an HPLC purity of 98.7%.

[0069] 1H NMR (400MHz, DMSO-d6) δ7.8(t,J=7.0Hz,1H),7.7(d,J=8.9Hz,2H),7.6(t,J=7.9Hz,3H),7.6–7.5(m,3H), 7.4–7.3(m,3H),6.9(dd,J=8.1,1.6Hz,1H),4.2(dd,J=14.5,4.1Hz,1H),4.0–3.8(m,3H),3.7–3.5(m,1H).

[0070] 13 C NMR (101MHz, DMSO) δ 160.6 (t, J C-F =31.3Hz),160.5,156.4,153.2,136.8,135.2,132.1,131.9,129.3,128.8, 127.9,127.8,127.6,127.0,125.2,123.2,122.0,120.1,118.3,117.0(t,J C-F =250.4Hz), 116.6, 50.6 (d, J) C-F =7.0Hz), 47.4(d,J C-F =5.0Hz), 33.4(t,J C-F =20.2Hz).

[0071] 19 F NMR (376MHz, DMSO-d6) δ-108.3 (d, J = 262.4Hz, 1F), -112.7 (d, J = 262.3Hz, 1F).

[0072] Example 9 1-(4-(tert-butyl)phenyl)-3,3-difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidine-2-one

[0073]

[0074] Compound (I) phenyl-3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) N-allyl-2-bromo-N-(4-(tert-butyl)phenyl)-2,2-difluoroacetamide (138.0 mg, 0.4 mmol), and compound (III) DABSO (96.1 mg, 0.4 mmol) were added to the reaction mixture equipped with a magnetic stirrer. Acetonitrile (2.0 mL) was added to the mixture. After purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 12 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 8:1 to obtain the target product with a yield of 66% and an HPLC purity of 98.2%.

[0075] 1 H NMR(400MHz, DMSO-d6)δ7.8(ddd,J=8.7,7.3,1.6Hz,11H),7.6(dd,J=8.4,1.1Hz,1H),7.6–7.5(m,7H),7.4–7.3(m,3H),6 .9(dd,J=8.2,1.5Hz,1H),4.2(dd,J=14.5,4.2Hz,1H),3.9(t,J=9.3Hz,1H),3.9–3.8(m,2H),3.7–3.5(m,0H),1.3(s,9H).

[0076] 13 C NMR(101MHz,DMSO)δ160.5,160.4(t,J C-F =30.3Hz),156.4,153.2,148.7,135.2,135.0,132.1,129.3,128.8,127 .9,127.8,127.6,127.0,125.7,125.2,123.2,120.1,120.0,117.1(t,J C-F =249.4Hz), 116.6, 50.7 (d, J) C-F =7.0Hz), 47.6(d,J C-F =6.0Hz), 34.2, 33.3(t,J C-F =20.2Hz), 31.0.

[0077] 19 FNMR(376MHz, DMSO-d6)δ-108.2(d,J=261.8Hz,1F),-112.7(d,J=262.1Hz,1F).

[0078] Example 10 1-(4-chloro-3-methoxyphenyl)-3,3-difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidine-2-one

[0079]

[0080] Compound (I) phenyl-3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) N-allyl-2-bromo-N-(3-chloro-4-methoxyphenyl)-2,2-difluoroacetamide (141.2 mg, 0.4 mmol), and compound (III) DABSO (96.1 mg, 0.4 mmol) were added to the mixture with magnetic stirring. Acetonitrile (2.0 mL) was added to the mixture. After purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 14 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 7:1 to obtain the target product with a yield of 64% and an HPLC purity of 98.5%.

[0081] 1 H NMR (400MHz, CDCl3) δ7.6 (ddd, J=8.6, 7.2, 1.6Hz, 1H), 7.5 (d, J=2.5Hz, 1H), 7 .5–7.4(m,3H),7.4(d,J=8.4Hz,1H),7.3(dd,J=8.1,4.3Hz,2H),7.2–7.2(m,2 H),7.0(dd,J=8.2,1.6Hz,1H),6.8(dd,J=8.6,2.5Hz,1H),4.0(t,J=3.3Hz,,1 H), 4.0 (dd, J = 14.0, 3.3Hz, 1H), 3.8 (s, 3H), 3.8–3.7 (m, 2H), 3.3–3.1 (m, 1H).

[0082] 13 C NMR(101MHz,CDCl3)δ161.4,160.8(t,J C-F =30.3Hz),156.7,155.2,153.7,137.1,135.6,131.4,130.1,130.1,129.7, 128.3,128.1,128.0,127.0,125.4,123.7,120.1,119.7,117.1,116.4(t,J C-F=251.4Hz),111.8,104.7,56.3,51.8(d,J C-F =7.0Hz), 48.0(d,J C-F =6.0Hz), 34.5(t,J C-F =21.2Hz).

[0083] 19 F NMR (376MHz, CDCl3) δ-109.9 (d, J = 266.4Hz, 1F), -114.5 (d, J = 266.4Hz, 1F).

[0084] Example 11 3,3-Difluoro-1-(naphth-2-yl)-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidone-2-one

[0085]

[0086] Compound (I) phenyl-3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) N-allyl-2-bromo-2,2-difluoro-N-(naphthyl-2-yl)acetamide (135.6 mg, 0.4 mmol), and compound (III) DABSO (96.1 mg, 0.4 mmol) were added to a reaction mixture equipped with a magnetic stirrer. Dimethyl sulfoxide (2.0 mL) was added to the mixture. After purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 35 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 9:1 to obtain the target product with a yield of 40% and an HPLC purity of 98.8%.

[0087] 1H NMR (400MHz, DMSO-d6) δ8.0(d,J=7.2Hz,2H),8.0(t,J=8.4Hz,2H),7.9(d,J=9.2Hz,1 H),7.8(t,J=7.9Hz,1H),7.6(d,J=8.4Hz,1H),7.5(dd,J=15.4,7.2Hz,4H),7.5(d,J=4 .1Hz,1H),7.4(t,J=6.7Hz,2H),6.9(d,J=8.1Hz,2H),4.2(dd,J=14.5,4.0Hz,1H),4. 1(t,J=9.4Hz,1H),4.0(t,J=9.0Hz,1H),3.9(dd,J=14.5,9.6Hz,1H),3.7–3.6(m,1H).

[0088] 13 C NMR (101MHz, DMSO) δ161.1,160.6,156.5,153.2,135.3,135.3,132.8,132.2,130.9,129.4,128.9,128.9 ,128.0,127.9,127.8,127.7,127.6,127.1,127.0,126.2,125.3,123.2,120.2,119.4,117.8,117.3(t,J C-F =258.4Hz),116.7,50.6,47.9,33.4(t,J C-F =20.2Hz).

[0089] 19 F NMR (376MHz, DMSO-d6) δ-108.2 (d, J=261.8Hz, 1F), -112.6 (d, J=261.8Hz, 1F).

[0090] Example 12 1-(3,5-dimethylphenyl)-3,3-difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidine-2-one

[0091]

[0092] Compound (I) phenyl-3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) N-allyl-2-bromo-N-(3,5-dimethylphenyl)-2,2-difluoroacetamide (126.8 mg, 0.4 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 purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 13 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 8:1 to obtain the target product with a yield of 87% and an HPLC purity of 98.2%.

[0093] 1 H NMR (400MHz, DMSO-d6) δ7.8(t,J=7.8Hz,1H),7.6(d,J=8.2Hz,1H),7.5(t,J=4.2Hz,2H),7.5(d,J=6.3Hz,1H),7.4(dd,J=7 .5,4.4Hz,3H),7.2(s,2H),7.0–6.9(m,2H),4.2(dd,J=14.6,4.2Hz,1H),3.9(t,J=9.4Hz,1H),3.8–3.7(m,3H),2.3(s,6H). 13 C NMR(101MHz,DMSO)δ161.1,160.8(t,J C-F =30.3Hz),156.9,153.5,138.7,137.7,135.7,132.4,129.7,129.3,128 .3,128.2,128.1,128.0,127.3,125.6,123.3,120.4,118.3,117.5(t,J C-F =251.4Hz), 117.0, 50.9(d,J) C-F =7.0Hz), 48.0(d,J C-F =6.0Hz), 33.7(t,J C-F =20.2Hz), 21.3.

[0094] 19 FNMR(376MHz, DMSO-d6)δ-108.3(d,J=261.6Hz,1F),-112.9(d,J=261.6Hz,1F).

[0095] Example 13 1-Cyclopentyl-3,3-difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidine-2-one

[0096]

[0097] Compound (I) phenyl-3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) N-allyl-2-bromo-N-cyclopentyl-2,2-difluoroacetamide (168.6 mg, 0.6 mmol), and compound (III) DABSO (144.2 mg, 0.6 mmol) were added to a reaction mixture equipped with a magnetic stirrer. Acetonitrile (2.0 mL) was added to the mixture, and after purging with nitrogen three times, the reaction system was irradiated under a white light with a power of 25 W and stirred at 30 °C for 18 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 10:1 to obtain the target product with a yield of 45% and an HPLC purity of 98.0%.

[0098] 1 H NMR (400MHz, DMSO-d6) δ7.8(t,J=7.8Hz,1H),7.6(d,J=8.3Hz,1H),7.5(d,J=4.6Hz,3H),7.4(t,J=6.7Hz,3H),6.9(d,J=8.1Hz,1H),4.3(t,J =7.5Hz,1H),4.1(d,J=14.4Hz,1H),3.7(dd,J=14.6,9.2Hz,1H),3.4(d,J=7.7Hz,2H),3.3(d,J=6.9Hz,1H),1.9–1.7(m,2H),1.7–1.4(m,6H).

[0099] 13 C NMR (101MHz, DMSO) δ 161.1 (t, J C-F =30.3Hz),160.7,156.5,153.2,135.2,132.3,129.4,128.8,128.1,127.8,127.5,126.8,125.2,122.9,120.3,117.7(t,J C-F =255.4Hz),116.7,52.7,50.5,(d,J C-F =7.0Hz), 42.7(d,J C-F =7.0Hz), 34.0(t,J C-F=21.2Hz),28.4,28.3,24.2,24.1.

[0100] 19 F NMR (376MHz, DMSO-d6) δ-110.1 (d, J = 260.7Hz, 1F), -113.5 (d, J = 260.3Hz, 1F).

[0101] Example 14 1-(4-(benzyloxy)phenyl)-3,3-difluoro-4-((2-oxo-4-phenyl-2H-chromen-3-yl)sulfonyl)methyl)pyrrolidone-2-one

[0102]

[0103] Compound (I) phenyl 3-phenylpropionate (47.2 mg, 0.2 mmol), compound (II) N-allyl-N-(4-(benzyloxy)phenyl)-2-bromo-2,2-difluoroacetamide (197.5 mg, 0.5 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 purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 13 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 7:1 to obtain the target product with a yield of 61% and an HPLC purity of 98.7%.

[0104] 1 H NMR (400MHz, DMSO-d6) δ7.8(t,J=7.8Hz,1H),7.6(d,J=8.4Hz,1H),7.5(d,J=7.5Hz,4H),7.5(d,J=7.2Hz,3H),7.4–7 .3(m,6H),7.1(d,J=8.5Hz,2H),6.9(d,J=8.3Hz,1H),5.1(s,2H),4.2–4.0(m,1H),3.9–3.7(m,2H),3.6–3.4(m,1H).

[0105] 13 C NMR(101MHz,DMSO)δ160.6,160.5(t,J C-F=30.3Hz),156.5,156.3,153.2,136.8,135.3,132.2,130.7,129.4,128.9,128.4, 128.0,127.9,127.8,127.7,127.7,127.0,125.2,123.2,122.1,120.2,117.3(t,J C-F =251.4Hz),116.7,115.2,69.4,50.7,47.9,33.6(t,J C-F =21.2Hz).

[0106] 19 FNMR(376MHz, DMSO-d6)δ-108.2(d,J=261.6Hz,1F),-112.6(d,J=261.7Hz,1F).

[0107] Example 15 Phenyl-2-(((4,4-difluoro-5-oxo-1-phenylpyrrolidine-3-yl)methyl)sulfonyl)but-2-enoate

[0108]

[0109] Compound (I) phenyl butyryl ester (32.0 mg, 0.2 mmol), compound (II) 2-bromo-2,2-difluoro-N-phenylacetamide (115.6 mg, 0.4 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, and after purging with nitrogen three times, the reaction system was irradiated with blue light at a power of 25 W and stirred at 30 °C for 14 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaCl solution, separated into layers, dried with anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using petroleum ether / ethyl acetate at a volume ratio of 10:1 to obtain the target product with a yield of 33% and an HPLC purity of 98.1%.

[0110] 1H NMR(400MHz, DMSO-d6)δ8.1(dd,J=8.1,1.5Hz,1H),7.8(ddd,J=8.6,7.2,1.5 Hz,1H),7.7(d,J=7.6Hz,2H),7.5(d,J=8.6Hz,1H),7.5(t,J=8.0Hz,2H),7.3( t,J=7.4Hz,1H),4.2(dd,J=14.6,5.0Hz,1H),4.1(ddd,J=10.2,8.6,1.7Hz,1 H),4.0–4.0(m,1H),3.9(dd,J=14.6,8.4Hz,1H),3.7–3.5(m,1H),3.0(s,3H).

[0111] 13 C NMR(101MHz,DMSO)δ160.9,160.7(t,J C-F =30.2Hz),156.2,152.6,137.6,135.2,129.1,127.6,126.2,125.3,123.1,120.3,119.5,117.2(t,J C-F =249.5Hz), 116.7, 51.1 (d, J) C-F =7.0Hz), 47.6(d,J C-F =7.0Hz), 33.7(t,J C-F =21.2Hz), 14.7.

[0112] 19 F NMR (376MHz, DMSO-d6) δ-107.8 (d, J = 262.3Hz, 1F), -112.6 (d, J = 262.2Hz, 1F).

[0113] Example 16 Antitumor activity test:

[0114] The effects of the compounds on the proliferation of MCF-7 and 4T1 cells are analyzed below:

[0115] Cell viability was determined using the MTT assay. MCF-7 cells were seeded in DMEM medium containing 10% FBS and 1% penicillin-streptomycin mixture and cultured in a 37°C incubator with 5% CO2. 4T1 cells were seeded in 87% RPMI 1640 medium, 10% serum, 1% Glutamax, 1% Sodium Pyruvate 100mM Solution, and 1% Non-essential Amino Acids and cultured in a 37°C incubator with 5% CO2.

[0116] Logarithmic growth phase MCF-7 cells and 4T1 cells were seeded into 96-well plates (100 μL, 8 × 10⁻⁶ cells per well). 4 Cells were incubated at 37°C for 24 h with different compounds at a concentration of 20 μM each for 48 h (three replicates for each concentration), with the untreated group serving as a blank control. Then, 10 μL of 5 mg / mL MTT solution was added to each well, and the cells were incubated at 37°C for 4 h with 5% CO2. After incubation, the supernatant was discarded, and 100 μL of LDMSO was added to each well. The cells were shaken at 500 rpm for 10 min, and the absorbance was measured at 492 nm. The formula for cell viability detection is:

[0117] Cell viability (%) = (average value of OD drug-treated group / average value of OD control group) × 100%.

[0118] 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 below:

[0119] The test results are shown in Table 1.

[0120] Table 1. Antitumor activity of compounds IV-a to IV-e at a concentration of 20 μM.

[0121]

[0122]

[0123] Note: Dihydroxyisoflavone (20 μM) is the control drug, metformin (2.5 mM) is the control drug, and CK is the blank control.

[0124] Table 1 shows that the antitumor activity test results indicate that, at a concentration of 20 μM, the difluoroaminosulfonyl coumarin derivatives IV-a to IV-e of the present invention all exhibited certain inhibitory activity against the tested targets. Among them, compounds IV-d and IV-e showed better inhibitory activity against MCF-7 and 4T1 cells.

[0125] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A method for photocatalytic preparation of coumarin derivatives from three components, characterized in that... The propynate esters represented by formula (I) and the 2-bromo-2,2-difluoro-represented by formula (II) N -Arylacetamide compounds, DABSO of formula (III) was added to the reaction solvent, and the reaction was carried out under nitrogen protection and light irradiation with stirring. After the reaction was completed, the reaction solution was post-treated to obtain the difluoroaminosulfonyl / bicyclized coumarin derivative of the target compound of formula (IV). The reaction equation is as follows: ； The DABSO is a bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct; In formulas (I) and (IV), R is selected from H, C1-C4 alkyl, halogen group, or trifluoromethyl; 1 R 2 All are selected from phenyl; The reaction solvent is selected from acetonitrile; The light source is blue light, white light, or violet light.

2. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 1, characterized in that... The light source is blue light.

3. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 1, characterized in that... The reaction temperature is 20~35℃.

4. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 3, characterized in that... The reaction temperature is 25~30℃.

5. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 1, characterized in that... The reaction time is 10~18h.

6. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 5, characterized in that... The reaction time is 12-13 hours.

7. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 1, characterized in that... The propynate esters represented by formula (I) and the 2-bromo-2,2-difluoro-represented by formula (II) N -Arylacetamide compounds, the molar ratio of the three components of DABSO shown in formula (III) is 1:1.5~3.0:1.5~3.

0.

8. The method for photocatalytic preparation of coumarin derivatives using a three-component system as described in claim 7, characterized in that... The propynate esters represented by formula (I) and the 2-bromo-2,2-difluoro-represented by formula (II) N -Arylacetamide compounds, the molar ratio of the three components of DABSO shown in formula (III) is 1:2:

2.

9. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 1, characterized in that... The post-treatment process of the reaction solution is as follows: the reaction solution is quenched with saturated sodium bicarbonate solution, washed with saturated brine, extracted with ethyl acetate, the combined organic layers are dried with anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, and the crude product is purified by column chromatography to obtain the target compound.

10. The method for photocatalytic preparation of coumarin derivatives from three components as described in claim 9, characterized in that... The eluent used for column separation and purification is a mixture of petroleum ether and ethyl acetate in a volume ratio of 6 to 10:

1.

11. Coumarin derivatives prepared by the method according to any one of claims 1 to 10.

12. The application of the coumarin derivative as described in claim 11, characterized in that... The coumarin derivatives are used to prepare inhibitors that suppress MCF-7 or 4T1 tumor cells.

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