3-hydroxyfluorenone compound as well as synthesis method and anticancer activity thereof

Abstract

The invention discloses a 3-hydroxyfluorenone compound as well as a synthesis method and anticancer activity thereof, and belongs to the technical field of organic synthesis and drug discovery. The preparation method comprises the following steps: mixing an enaminone compound 1, a 1-substituted cyclopropanol compound 2, a catalyst, an additive and an organic solvent, heating and reacting to prepare the 3-hydroxyfluorenone compound 3, and the structural general formula of the 3-hydroxyfluorenone compound 3 is shown as # imgabs0. The compound provided by the invention has the activity of obviously inhibiting proliferation of three cancer cells, namely A-549, HCT-116 and Hela, so that the compound provided by the invention has the anti-cancer activity on lung cancer, colon cancer and cervical cancer, and has potential medicinal value.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis and drug discovery, and particularly relates to 3-hydroxyfluorenone compounds, a synthesis method thereof, and anticancer activity. Background Art

[0002] The fluorenone skeleton is widely present in natural products and synthetic compounds, and these compounds often possess significant pharmacological activities such as antiviral, anticancer, antifungal, antidepressant, diuretic, and antimalarial properties. Furthermore, many fluorenone derivatives possess unique and easily tunable optical and physicochemical properties, leading to their widespread application in electroluminescent polymers, semiconductors, light-emitting diodes, dyes, optical brighteners, and liquid crystal materials. It is particularly noteworthy that many fluorenone derivatives with biological activity or fluorescent properties contain at least one hydroxyl group on their core skeleton, indicating that the hydroxyl group plays a significant role in the function of the parent compound.

[0003] Several effective methods for constructing fluorenone backbones have been reported in the literature. However, these methods often suffer from difficulties in substrate preparation, cumbersome procedures, harsh reaction conditions, and the generation of toxic halogenated byproducts, limiting their practical applications. Furthermore, no methods specifically designed for the synthesis of 3-hydroxy-substituted fluorenone derivatives have been reported.

[0004] Therefore, synthesizing new 3-hydroxyfluorenone compounds, studying their biological activity and medicinal value, and developing new green and efficient methods to synthesize such compounds from simple and readily available raw materials through simple steps have very important theoretical significance and practical prospects. Summary of the Invention

[0005] In order to solve the problems existing in the prior art, one of the purposes of the present invention is to provide a new class of 3-hydroxyfluorenone compounds. Studies have shown that this class of compounds has good anti-cancer activity.

[0006] A second object of the present invention is to provide the use of 3-hydroxyfluorenone compounds in the preparation of anticancer drugs.

[0007] A third object of the present invention is to provide a pharmaceutical composition for treating lung cancer, colon cancer and / or cervical cancer, wherein the active ingredient is the 3-hydroxyfluorenone compound provided by the present invention.

[0008] A fourth object of the present invention is to provide a method for synthesizing 3-hydroxyfluorenone compounds.

[0009] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] 3-Hydroxyfluorenone compounds, the general structural formula of which is:

[0011]

[0012] where R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, trifluoromethyl, phenyl, C 1-4 Alkoxycarbonyl, cyano or methylenedioxy, R 1 is mono- or di-substituted; or R 1 Together with the benzene ring, it forms a naphthyl group; R 2 is phenyl or substituted phenyl, the substituent on the substituted phenyl is a mono- or di-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen.

[0013] Furthermore, in the above general structure, in the most preferred case, the following specific structures are selected:

[0014]

[0015] Experiments designed by the present invention demonstrate that the compounds provided herein have the ability to inhibit the proliferation of three cancer cells: A-549, HCT-116, and Hela. This suggests that the compounds provided herein can serve as active ingredients in drugs for treating cancers such as lung cancer, colon cancer, and cervical cancer. In particular, the preferred compounds described above significantly inhibit the growth and proliferation of A-549, HCT-116, and Hela, suggesting that these compounds, as active ingredients in anticancer drugs, have the potential to prevent, treat, and inhibit the progression of lung cancer, colon cancer, and cervical cancer.

[0016] The aforementioned 3-hydroxyfluorenone compounds are used in the preparation of anticancer drugs, wherein the anticancer drugs are used for lung cancer, colon cancer and / or cervical cancer.

[0017] A pharmaceutical composition for treating lung cancer, colon cancer and / or cervical cancer, wherein the active ingredient includes the aforementioned 3-hydroxyfluorenone compound.

[0018] The present invention also provides a method for synthesizing the above-mentioned 3-hydroxyfluorenone compound, which is prepared using an enaminone compound and a 1-substituted cyclopropanol compound as raw materials; the method comprises the following steps: mixing an enaminone compound 1, a 1-substituted cyclopropanol compound 2, a catalyst, an additive, and an organic solvent, and heating the mixture to react to obtain a 3-hydroxyfluorenone compound 3. The reaction equation is:

[0019]

[0020] Where: R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, trifluoromethyl, phenyl, C 1-4 Alkoxycarbonyl, cyano or methylenedioxy, R 1is a mono- or di-substituted, or R 1 Together with the benzene ring, it forms a naphthyl group; R 2 is phenyl or substituted phenyl, the substituent on the substituted phenyl is a mono- or di-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen.

[0021] Furthermore, in the above technical solution, the additive is selected from a mixture of silver hexafluoroantimonate and copper acetate, a mixture of silver hexafluoroantimonate and copper acetate monohydrate, or a mixture of silver hexafluoroantimonate and silver acetate.

[0022] Furthermore, in the above technical solution, the catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([RhCp*Cl2]2) or bis(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III) ([RhCp*(MeCN)3](SbF6)2).

[0023] Furthermore, in the above technical solution, the molar ratio of the enaminone compound 1, the 1-substituted cyclopropanol compound 2, the catalyst and the additive is 1:1-2:0.03-0.05:0.5-2.5.

[0024] Furthermore, in the above technical solution, the organic solvent is selected from methanol, ethanol or tetrahydrofuran.

[0025] Furthermore, in the above technical solution, the temperature of the temperature-raising reaction is selected from 60-110°C.

[0026] Furthermore, in the above technical solution, the reaction is carried out in air or an inert gas atmosphere.

[0027] (1) The 3-hydroxyfluorenone compounds provided by the present invention were screened for compounds having various substituents and verified by anticancer activity tests. The compounds provided by the present invention have the activity of significantly inhibiting the proliferation of three cancer cells, namely A-549, HCT-116 and Hela, indicating that the compounds of the present invention have anticancer activity against lung cancer, colon cancer and cervical cancer, and have potential medicinal value;

[0028] (2) The synthesis method of 3-hydroxyfluorenone compounds provided by the present invention is completed by a one-pot cascade reaction of enaminones and 1-substituted cyclopropanols, which is a simple and efficient process;

[0029] (3) The synthesis method of 3-hydroxyfluorenone compounds provided by the present invention has the characteristics of cheap and readily available raw materials, mild reaction conditions, simple operation, wide application range, and good functional group tolerance. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1This is the X-ray single crystal diffraction pattern of compound 3u in Example 3. DETAILED DESCRIPTION

[0031] The above contents of the present invention are further described in detail below through examples, but this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above contents of the present invention fall within the scope of the present invention.

[0032] Example 1

[0033]

[0034] Compound 1a, compound 2a, catalyst, additive 1, additive 2, and an organic solvent were added sequentially to a 15 mL reaction tube. The tube was then sealed and placed in an oil bath with stirring and heating. After the reaction was completed, the mixture was cooled to room temperature and quenched with saturated aqueous NH4Cl solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried, and filtered. The filtrate was concentrated and separated on a silica gel column (petroleum ether / ethyl acetate = 6 / 1) to obtain a yellow solid product 3a.

[0035] By changing the reaction conditions such as catalyst, additive, organic solvent and temperature, the reaction results are as follows:

[0036] Table 1 Synthesis of 3a under different conditions a

[0037]

[0038]

[0039] Example 2

[0040]

[0041] To a 15 mL pressure tube were added 1a (35.0 mg, 0.2 mmol), 2a (59.3 mg, 0.4 mmol), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol), silver hexafluoroantimonate (13.7 mg, 0.04 mmol), acetonitrile (72.7 mg, 0.4 mmol), methanol (2 mL), and THF (0.1 mL). The reaction tube was evacuated, filled with argon, sealed, and placed in an oil bath at 100°C for 12 h. After completion of the reaction, the reaction system was cooled to room temperature and quenched by addition of saturated aqueous NH4Cl. The reaction was extracted three times with ethyl acetate, and the organic phases were combined, dried, filtered, and the filtrate concentrated. The filtrate was then separated on a silica gel column (petroleum ether / ethyl acetate = 6 / 1) to afford 3a (34.3 mg, 63%) as a yellow solid. 1H NMR (600MHz, DMSO-d6): δ10.94(br s,1H),7.70(d,J=7.2Hz,1H),7.60-7.56(m,4H),7.50(s,1H),7.43(t,J=7.8Hz,2H),7.38(t,J=7.2Hz,1H),7.34(t,J=7.2Hz,1H),7.26(s,1H). 13 C NMR (150MHz, DMSO-d6): δ191.9,161.7,145.7,143.2,137.9,135.2,135.1,130.0,1 29.5,128.6,128.5,127.6,127.1,125.6,123.8,121.2,109.3.HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 13 O2273.0910;Found273.0913.

[0042] Example 3

[0043] According to the method and steps of Example 2, various 3-hydroxyfluorenone compounds 3 were synthesized by changing reactant 1 and reactant 2. The specific results are as follows:

[0044] Table 2 Synthesis of 3-hydroxyfluorenone compound 3 a,b

[0045]

[0046]

[0047] Representative product characterization data are as follows:

[0048] 3-Hydroxy-6-methyl-2-phenyl-9H-fluoren-9-one(3b)

[0049] 1 H NMR (600MHz, DMSO-d6): δ10.91 (br s,1H),7.57(d,J=7.8Hz,2H),7.50(s,1H),7.46-7.41(m,4H),7.34(t,J=7.2Hz,1H),7.22(s,1H),7.17(d,J=7.2Hz,1H),2.41(s,3H). 13C NMR(150MHz,DMSO-d6):δ191.7,161.4.,145.8,145.6,143.6,138.0,132.9,130.2,129.5,128.5,128.4,127.5,127.0,126.2,123.8,122.0,109.2,22.1.HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 14 NaO2309.0886;Found 309.0884.

[0050] 6-Ethyl-3-hydroxy-2-phenyl-9H-fluoren-9-one(3c)

[0051] 1 H NMR(400 MHz,DMSO-d6):δ10.91(br s,1H),7.58(d,J=7.6 Hz,2H),7.54(s,1H),7.49-7.41(m,4H),7.34(t,J=7.2 Hz,1H),7.25(s,1H),7.20(d,J=7.6 Hz,1H),2.71(q,J=7.6 Hz.2H),1.25(t,J=7.6 Hz,3H). 13 C NMR(100 MHz,DMSO-d6):δ191.7,161.4,152.0,145.7,143.7,138.0,133.1,129.5,129.1,128.5,128.3,127.5,127.0,126.2,123.9,120.9,109.2,29.1,15.7.HRMS(ESI)m / z:[M+Na] + Calcd forC 21 H 16 NaO2323.1043;Found 323.1044.

[0052] 3-Hydroxy-6-isopropyl-2-phenyl-9H-fluoren-9-one(3d)

[0053] 1H NMR(600 MHz,DMSO-d6):δ10.89(br s,1H),7.59-7.58(m,3H),7.49(d,J=7.2Hz,1H),7.47(s,1H),7.43(t,J=7.8 Hz,2H),7.34(t,J=7.8 Hz,1H),7.27(s,1H),7.24(d,J=7.8 Hz,1H),3.03-2.99(m,1H),1.27(d,J=7.2 Hz,6H). 13 C NMR(150 MHz,DMSO-d6):δ191.7,161.4,156.6,145.7,143.7,137.9,133.3,129.5,128.5,128.3,127.7,127.5,127.0,126.2,124.0,119.6,109.3,34.4,23.9.HRMS(ESI)m / z:[M+Na] + Calcd forC 22 H 18 NaO2337.1199;Found 337.1195.

[0054] 3-Hydroxy-2,6-diphenyl-9H-fluoren-9-one(3e)

[0055] 1 H NMR(600 MHz,DMSO-d6):δ10.99(br s,1H),8.02(s,1H),7.83(d,J=7.2 Hz,2H),7.67(dd,J1=7.2 Hz,J2=1.2 Hz,1H),7.64(d,J=7.2 Hz,1H),7.59(d,J=6.6Hz,2H),7.54(t,J=7.2 Hz,2H),7.51(s,1H),7.47(t,J=7.2 Hz,1H),7.43(d,J=7.8 Hz,2H),7.38(s.1H),7.34(t,J=7.2 Hz,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.5,161.8,147.0,145.5,144.2,139.7,137.9,134.2,129.61,129.55,129.49,129.0,128.7,128.6,128.3,127.60,127.57,127.0,124.3,119.7,109.8.HRMS(ESI)m / z:[M+Na] + Calcd forC25 H 16 NaO2371.1043;Found 371.1046.

[0056] 6-Fluoro-3-hydroxy-2-phenyl-9H-fluoren-9-one(3f)

[0057] 1 H NMR(600 MHz,DMSO-d6):δ11.07(br s,1H),7.64(dd,J1=9.0 Hz,J2=2.4 Hz,1H),7.61(dd,J1=7.8 Hz,J2=4.8 Hz,1H),7.57(d,J=7.2 Hz,2H),7.49(s,1H),7.43(t,J=7.8 Hz,2H),7.34(t,J=7.2 Hz,1H),7.32(s.1H),7.18-7.15(m,1H). 13 CNMR(150 MHz,DMSO-d6):δ190.4,167.0(d, 1 J C-F =250.4 Hz),161.7,146.5(d, 3 J C-F =9.9 Hz),144.2,137.8,131.5,129.5,129.2,128.6,127.7,127.0,126.09,126.08(d, 3 J C-F =11.0 Hz),116.1(d, 2 J C-F =23.0 Hz),110.0,109.6(d, 2 J C-F =24.2 Hz). 19 FNMR(376 MHz,DMSO-d6):δ-104.15(td,J1=9.4 Hz,J2=5.3 Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 12 FO2291.0816;Found 291.0821.

[0058] 6-Chloro-3-hydroxy-2-phenyl-9H-fluoren-9-one(3g)

[0059] 1H NMR(600 MHz,DMSO-d6):δ11.07(br s,1H),7.85(d,J=1.2 Hz,1H),7.58-7.54(m,3H),7.50(s.1H),7.44-7.41(m,3H),7.35(t,J=7.8 Hz,1H),7.31(s.1H). 13 C NMR(150MHz,DMSO-d6):δ190.6,161.7,145.3,144.5,139.9,137.7,133.8,129.6,129.5,129.3,128.6,127.7,127.3,125.8,125.2,121.8,110.0.HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 12 ClO2307.0520;Found 307.0518.

[0060] 6-Bromo-3-hydroxy-2-phenyl-9H-fluoren-9-one(3h)

[0061] 1 H NMR(400 MHz,DMSO-d6):δ11.11(br s,1H),8.01(d,J=1.2 Hz,1H),7.59-7.56(m,3H),7.51(s,1H),7.48(d,J=7.6 Hz,1H),7.43(t,J=7.2 Hz,2H),7.34(t,J=6.8 Hz,1H),7.31(s,1H). 13 C NMR(100 MHz,DMSO-d6):δ190.8,161.8,145.3,144.5,137.7,134.1,132.6,129.5,129.3,129.0,128.6,127.7,127.3,125.6,125.4,124.6,110.1.HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 12 BrO2351.0015;Found351.0022.

[0062] 3-Hydroxy-6-iodo-2-phenyl-9H-fluoren-9-one(3i)

[0063] 1H NMR(600 MHz,DMSO-d6):δ11.00(br s,1H),8.15(s,1H),7.77(d,J=7.8 Hz,1H),7.57(d,J=7.2 Hz,2H),7.50(s.1H),7.43(t,J=7.8 Hz,2H),7.35-7.31(m,2H),7.29(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.2,161.7,144.9,144.6,138.7,137.8,134.5,130.1,129.5,129.2,128.6,127.7,127.3,125.5,125.2,110.0,103.5.HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 11 INaO2420.9696;Found 420.9699.

[0064] 3-Hydroxy-2-phenyl-6-(trifluoromethyl)-9H-fluoren-9-one(3j)

[0065] 1 H NMR(600 MHz,DMSO-d6):δ11.15(br s,1H),8.10(s,1H),7.74-7.71(m,2H),7.59-7.57(m,2H),7.53(s,1H),7.44(t,J=7.2 Hz,2H),7.40(s,1H),7.36(t,J=7.8Hz,1H). 13 C NMR(150 MHz,DMSO-d6):δ190.5,162.2,144.7,144.1,138.3,137.7,134.5(q, 2 J C-F =31.8 Hz),129.6,129.5,128.6,127.7,127.5,127.2(q, 3 J C-F =3.3 Hz),125.6,124.3(q, 1 J C-F =271.2 Hz),124.2,118.2(q, 3 J C-F =3.3 Hz),110.3. 19F NMR(565 MHz,DMSO-d6):δ-61.50(s).HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 12 F3O2341.0784;Found 341.0789.

[0066] Methyl 6-hydroxy-9-oxo-7-phenyl-9H-fluorene-3-carboxylate(3k)

[0067] 1 H NMR(600 MHz,DMSO-d6):δ11.09(br s,1H),8.06(s,1H),7.93(d,J=7.8 Hz,1H),7.64(d,J=7.8 Hz,1H),7.57(d,J=7.2 Hz,2H),7.49(s,1H),7.43(t,J=7.8Hz,2H),7.35(t,J=7.8 Hz,1H),7.29(s,1H),3.91(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ190.8,166.0,162.1,144.9,143.4,138.8,137.7,135.2,131.3,129.5,129.2,128.6,127.7,127.4,125.7,123.8,121.1,109.7,53.0.HRMS(ESI)m / z:[M+H] + Calcd forC 21 H 15 O4331.0965;Found 331.0963.

[0068] 6-Hydroxy-9-oxo-7-phenyl-9H-fluorene-3-carbonitrile(3l)

[0069] 1 H NMR(400 MHz,DMSO-d6):δ11.25(br s,1H),8.28(s,1H),7.87(d,J=7.6 Hz,1H),7.71(d,J=7.6 Hz,1H),7.57(d,J=7.6 Hz,2H),7.55(s,1H),7.43(t,J=7.6Hz,2H),7.37-7.33(m,2H). 13C NMR(150 MHz,DMSO-d6):δ190.0,162.0,144.2,143.3,138.1,137.2,134.3,129.4,129.1,128.2,127.4,127.3,125.0,124.3,123.8,118.4,116.4,109.9.HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 11 F3NNaO2320.0682;Found 320.0687.

[0070] 3-Hydroxy-2-phenyl-7-(trifluoromethyl)-9H-fluoren-9-one(3m)

[0071] 1 H NMR(600 MHz,DMSO-d6):δ11.17(s,1H),7.97(d,J=7.2 Hz,1H),7.94(d,J=7.8 Hz,1H),7.80(s,1H),7.59-7.57(m,3H),7.44(t,J=7.8 Hz,2H),7.38(s,1H),7.36(t,J=7.2 Hz,1H). 13 C NMR(150 MHz,DMSO-d6):δ190.2,162.0,146.8,144.4,137.6,135.9,132.2(q, 3 J C-F =4.4 Hz),130.1(q, 2 J C-F =32.9 Hz),129.8,129.5,128.6,127.8,127.6,125.9,124.3(q, 1 J C-F =270.3 Hz),122.1,120.1(q, 3 J C-F =3.3 Hz),110.3. 19 F NMR(376MHz,DMSO-d6):δ-61.19(s).HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 12 F3O2341.0784;Found341.0789.

[0072] 1-Chloro-6-hydroxy-7-phenyl-9H-fluoren-9-one(3n)

[0073] 1 H NMR(600 MHz,DMSO-d6):δ10.95(br s,1H),7.70(d,J=7.2 Hz,1H),7.59-7.56(m,3H),7.49(s,1H),7.43(t,J=7.2 Hz,2H),7.38(t,J=7.2 Hz,1H),7.34(t,J=7.2 Hz,1H),7.27(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ192.0,161.7,145.8,143.2,137.9,135.21,135.16,130.0,129.5,128.6,128.5,127.6,127.2,125.7,123.8,121.3,109.4.HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 12 ClO2307.0520;Found307.0517.

[0074] 1-Bromo-6-hydroxy-7-phenyl-9H-fluoren-9-one(3o)

[0075] 1 H NMR(600 MHz,DMSO-d6):δ10.96(br s,1H),7.69(d,J=7.2 Hz,1H),7.60-7.56(m,3H),7.49(s,1H),7.43(t,J=7.2 Hz,2H),7.38(t,J=7.2 Hz,1H),7.34(t,J=7.2 Hz,1H),7.27(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.9,161.7,145.8,143.2,137.9,135.2,135.1,130.0,129.5,128.6,128.5,127.6,127.2.125.6,123.8,121.3,109.3.HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 12 BrO2351.0015;Found315.0020.

[0076] 3-Hydroxy-6,7-dimethyl-2-phenyl-9H-fluoren-9-one(3p)

[0077] 1 H NMR(600 MHz,DMSO-d6):δ10.85(br s,1H),7.56(d,J=7.2 Hz,2H),7.45(s,1H),7.43-7.41(m,3H),7.34-7.31(m,2H),7.17(s,1H),2.32(s,3H),2.26(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ192.0,161.4,145.9,144.2,141.2,138.2,138.1,133.3,129.4,128.5,127.8,127.4,126.9,126.0,125.0,122.4,108.9,20.6,19.9.HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 16 NaO2323.1043;Found 323.1044.

[0078] 2,3-Dichloro-6-hydroxy-7-phenyl-9H-fluoren-9-one(3q)

[0079] 1 H NMR(600 MHz,DMSO-d6):δ11.19(s,1H),8.12(s,1H),7.75(s,1H),7.57(d,J=7.8 Hz,2H),7.53(s,1H),7.43(t,J=7.2 Hz,2H),7.36-7.34(m,2H). 13 C NMR(150 MHz,DMSO-d6):δ189.5,162.1,144.1,143.1,137.6,137.4,135.3,132.4,129.5,128.6,127.8,127.6,125.6,125.5,123.8,110.3.HRMS(ESI)m / z:[M+Na] + CalcdforC 19 H 10 Cl2NaO2362.9950;Found 632.9953.

[0080] 9-Hydroxy-8-phenyl-6H-fluoreno[3,4-d][1,3]dioxol-6-one(3r)

[0081] 1 H NMR(600 MHz,DMSO-d6):δ10.88(br s,1H),7.58(d,J=7.8 Hz,2H),7.48(s,1H),7.42(t,J=7.8Hz,2H),7.34(t,J=7.2 Hz,1H),7.18-7.17(m,2H),6.83(d,J=7.8Hz,1H),6.28(s,2H). 13 C NMR(150 MHz,DMSO-d6):δ189.8,161.2,154.1,142.1,142.0,137.8,130.1,129.5,128.5,127.6,127.0,126.5,122.1,119.7,111.3,108.0,103.5.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 13 O4317.0808;Found317.0806.

[0082] 3-Hydroxy-2-phenyl-11H-benzo[b]fluoren-11-one(3s)

[0083] 1 H NMR(400 MHz,DMSO-d6):δ11.06(br s,1H),8.19(s,1H),8.15(s,1H),8.07(d,J=7.8 Hz,1H),8.02(d,J=8.4 Hz,1H),7.65-7.60(m,3H),7.58-7.54(m,2H),7.45(t,J=7.2 Hz,2H),7.42(s,1H),7.36(t,J=7.2 Hz,1H). 13 C NMR(150 MHz,DMSO-d6):δ190.9,162.1,146.2,137.9,137.6,136.8,133.9,133.8,131.1,129.6,129.53,129.47,129.3,128.6,128.0,127.7,127.6,127.1,124.9,119.8,109.1.HRMS(ESI)m / z:[M+H] + Calcd forC 23H 15 O2323.1067;Found 323.1070.

[0084] 3-Hydroxy-2-(p-tolyl)-9H-fluoren-9-one(3u)

[0085] 1 H NMR(400 MHz,DMSO-d6):δ10.88(br s,1H),7.68(d,J=7.6 Hz,1H),7.60-7.55(m,2H),7.48-7.46(m,3H),7.37(td,J1=7.2 Hz,J2=0.8 Hz,1H),7.25(s,1H),7.23(d,J=8.0 Hz,2H),2.35(s,3H). 13 C NMR(100 MHz,DMSO-d6):δ192.0,161.6,145.5,143.3,136.8,135.2,135.1,134.9,129.9,129.3,129.1,128.5,127.0,125.6,123.8,121.2,109.3,21.2.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 15 O2287.1067;Found 287.1071.

[0086] 2-(4-Chlorophenyl)-3-hydroxy-9H-fluoren-9-one(3v)

[0087] 1 H NMR(600 MHz,DMSO-d6):δ11.10(br s,1H),7.70(d,J=7.2 Hz,1H),7.62-7.56(m,4H),7.51(s,1H),7.47(d,J=7.8 Hz,2H),7.39(t,J=7.8 Hz,1H),7.26(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.9,161.6,146.0,143.1,136.7,135.19,135.17,132.3,131.3,130.1,128.5,127.09,127.05,125.7,123.8,121.3,109.4.HRMS(ESI)m / z:[M+Na] + Calcdfor C 19 H11 ClNaO2329.0340;Found 329.0341.

[0088] 2-(4-Bromophenyl)-3-hydroxy-9H-fluoren-9-one(3w)

[0089] 1 H NMR(600 MHz,DMSO-d6):δ11.10(br s,1H),7.69(d,J=7.8 Hz,1H),7.62-7.54(m,6H),7.51(s,1H),7.39(t,J=7.2 Hz,1H),7.26(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.8,161.6,146.0,143.1,137.0,135.19,135.16,131.6,131.5,130.1,127.1,127.0,125.7,123.8,121.3,120.9,109.4.HRMS(ESI)m / z:[M+Na] + CalcdforC 19 H 11 BrNaO2372.9835;Found 372.9839.

[0090] 3-Hydroxy-2-(o-tolyl)-9H-fluoren-9-one(3x)

[0091] 1 H NMR(400 MHz,DMSO-d6):δ10.80(br s,1H),7.70(d,J=7.2 Hz,1H),7.61-7.59(m,2H),7.38(t,J=7.2 Hz,1H),7.27-7.21(m,5H),7.16(d,J=7.2 Hz,1H),2.16(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ192.0,161.7,146.1,143.3,138.1,136.7,135.2,135.1,130.2,130.1,129.9,129.3,127.9,127.5,126.1,125.2,123.8,121.2,108.8,20.1.HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 14NaO2309.0886;Found 309.0884.

[0092] 3-Hydroxy-2-(2-methoxyphenyl)-9H-fluoren-9-one(3y)

[0093] 1 H NMR(600 MHz,DMSO-d6):δ10.60(br s,1H),7.68(d,J=7.2 Hz,1H),7.59-7.55(m,2H),738-7.34(m,3H),7.24-7.22(m,2H),7.08(d,J=7.8 Hz,1H),7.00(t,J=7.2 Hz,1H),3.74(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ192.0,162.2,157.2,145.8,143.4,135.2,135.0,131.5,129.8,129.4,128.3,126.8,126.2,124.9,123.7,121.1,120.6,111.8,108.9,55.9.HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 15 O3303.1016;Found 303.1010.

[0094] 2-(2-Fluorophenyl)-3-hydroxy-9H-fluoren-9-one(3z)

[0095] 1 H NMR(600 MHz,DMSO-d6):δ11.05(br s,1H),7.72(d,J=7.8 Hz,1H),7.61-7.57(m,2H),7.46-7.39(m,4H),7.30(s,1H),7.28-7.25(m,2H). 13 C NMR(150MHz,DMSO-d6):δ191.8,162.2,159.9(d, 1 J C-F =245.0 Hz),146.6,143.1,135.2(d, 4 J C-F =3.3 Hz),132.2(d, 4 J C-F =2.1 Hz),130.12,130.06(d,3 J C-F =7.7 Hz),127.9,125.6(d, 2 J C-F =15.3 Hz),125.2,124.7(d, 4 J C-F =3.3 Hz),123.9,123.2,121.4,115.9(d, 2 J C-F =23.0 Hz),109.0. 19 FNMR(565 MHz,DMSO-d6):δ-113.57–-113.61(m).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 12 FO2291.0816;Found 291.0815.

[0096] 3-Hydroxy-2-(m-tolyl)-9H-fluoren-9-one(3aa)

[0097] 1 H NMR(600 MHz,DMSO-d6):δ10.89(br s,1H),7.68(d,J=7.2 Hz,1H),7.59-7.56(m,2H),7.48(s,1H),7.39-7.37(m,3H),7.31(t,J=7.8 Hz,1H),7.26(s,1H),7.15(d,J=7.2 Hz,1H),2.36(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ192.0,161.7,145.7,143.2,137.8,137.6,135.2,135.1,130.0,129.9,128.6,128.4,128.2,127.2,126.6,125.6,123.8,121.2,109.3,21.5.HRMS(ESI)m / z:[M+Na] + Calcd forC 20 H 14 NaO2309.0886;Found309.0892.

[0098] 3-Hydroxy-2-(3-methoxyphenyl)-9H-fluoren-9-one(3bb)

[0099] 1H NMR(600 MHz,DMSO-d6):δ10.94(br s,1H),7.69(d,J=7.8 Hz,1H),7.60-7.56(m,2H),7.51(s,1H),7.38(t,J=7.8 Hz,1H),7.34(t,J=7.8 Hz,1H),7.26(s,1H),7.15-7.14(m,2H),6.93-6.91(m,1H),3.81(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ191.9,161.7,159.5,145.8,143.2,139.2,135.2,135.1,130.0,129.5,128.4,127.2,125.6,123.8,121.8,121.3,115.1113.2,109.4,55.5.HRMS(ESI)m / z:[M+Na] + Calcd forC 20 H 14 NaO3325.0835;Found 325.0838.

[0100] 2-(3-Fluorophenyl)-3-hydroxy-9H-fluoren-9-one(3cc)

[0101] 1 H NMR(600 MHz,DMSO-d6):δ11.10(br s,1H),7.70(d,J=7.2 Hz,1H),7.61-7.57(m,2H),7.54(s,1H),7.49-7.42(m,3H),7.40-7.38(m,1H),7.27(s,1H),7.19-7.16(m,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.8,162.4(d, 1 J C-F =240.8 Hz),161.6,146.1,143.1,140.2(d, 3 J C-F =7.7 Hz),135.2,135.1,130.4(d, 3 J C-F =7.7 Hz),130.1,127.2,127.0,125.6,125.5(d, 4 J C-F =2.3 Hz),123.8,121.4,116.2(d, 2 JC-F =21.9 Hz),114.3(d, 2 J C-F =20.7 Hz),109.4. 19 F NMR(376 MHz,DMSO-d6):δ-113.67–-113.76(m).HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 11 FNaO2313.0635;Found 313.0632.

[0102] 2-(3-Chlorophenyl)-3-hydroxy-9H-fluoren-9-one(3dd)

[0103] 1 H NMR(600 MHz,DMSO-d6):δ11.07(br s,1H),7.71(d,J=7.8 Hz,1H),7.64(s,1H),7.61-7.57(m,2H),7.55-7.53(m,2H),7.46(t,J=7.8 Hz,1H),7.41-7.38(m,2H),7.28(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.8,161.8,146.2,143.1,140.0,135.2,133.2,130.4,130.1,129.2,128.1,127.4,127.2,126.8,125.6,123.9,121.4,109.5.HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 12 ClO2307.0520;Found307.0522.

[0104] 2-(3-Bromophenyl)-3-hydroxy-9H-fluoren-9-one(3ee)

[0105] 1H NMR(600 MHz,DMSO-d6):δ11.11(br s,1H),7.78(s,1H),7.71(d,J=7.8 Hz,1H),7.61-7.58(m,3H),7.53(dd,J1=7.8 Hz,J2=1.2 Hz,1H),7.52(s,1H),7.39(t,J=7.8Hz,2H),7.27(s,1H). 13 C NMR(150 MHz,DMSO-d6):δ191.8,161.7,146.2,143.1140.2,135.2,132.0,130.7,130.3,130.1,128.5,127.2,126.8,125.6,123.9,121.8,121.4,109.4.HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 11 BrNaO2372.9835;Found 372.9836.

[0106] 2-(3,4-Dimethoxyphenyl)-3-hydroxy-9H-fluoren-9-one(3ff)

[0107] 1 H NMR(400 MHz,DMSO-d6):δ10.84(br s,1H),7.67(d,J=7.6 Hz,1H),7.59-7.55(m,2H),7.52(s,1H),7.37(t,J=7.6 Hz,1H),7.24(s,1H),7.17-7.13(m,2H),7.00(d,J=7.0 Hz,1H),3.81(s,3H),3.80(s,3H). 13 C NMR(100 MHz,DMSO-d6):δ192.0,161.6,148.7,148.6,145.3,143.3,135.2,135.1,130.3,129.8,128.5,127.0,125.6,123.8,121.9,121.1,113.4,111.9,109.3,56.0.HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 17 O4333.1121;Found 333.1125.

[0108] 2-(3,4-Dichlorophenyl)-3-hydroxy-9H-fluoren-9-one(3gg)

[0109] 1 H NMR(600 MHz,DMSO-d6):δ11.15(br s,1H),7.85(s,1H),7.71(d,J=7.8 Hz,1H),7.67(d,J=8.4 Hz,1H),7.61-7.56(m,4H),7.40(t,J=7.2 Hz,1H),7.27(s,1H). 13 CNMR(150 MHz,DMSO-d6):δ191.7,161.7,146.4,143.0,138.4,135.21,135.19,131.3,131.2,130.7,130.2,130.1,129.8,127.2,125.6,123.9,121.5,109.5.HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 10 Cl2NaO2362.9950;Found 362.9954.

[0110] 3-Hydroxy-2-(m-tolyl)-11H-benzo[b]fluoren-11-one(3hh)

[0111] 1 H NMR(600 MHz,DMSO-d6):δ11.02(br s,1H),8.19(s,1H),8.14(s,1H),8.07(d,J=7.8 Hz,1H),8.02(d,J=7.8 Hz,1H),7.65-7.62(m,1H),7.56-7.54(m,2H),7.41-7.39(m,3H),7.32(t,J=7.8 Hz,1H),7.17(d,J=7.8 Hz,1H),2.37(s,3H). 13 CNMR(150 MHz,DMSO-d6):δ191.0,162.1,146.1,137.8,137.6,136.8,133.9.133.8,131.1,130.1,129.8,129.5,129.3,128.4,128.3,128.0,127.6,127.1,126.7,124.9,119.8,109.1,21.6.HRMS(ESI)m / z:[M+Na] +Calcd for C 24 H 16 NaO2359.1043;Found 359.1039.

[0112] 3-Hydroxy-6-methyl-2-(m-tolyl)-9H-fluoren-9-one(3jj)

[0113] 1 H NMR(600 MHz,DMSO-d6):δ10.85(br s,1H),7.49(s,1H),7.45-7.44(m,2H),7.37-7.36(m,2H),7.30(t,J=7.2 Hz,1H),7.21(s,1H),7.17-7.14(m,2H),2.41(s,3H),2.36(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ191.7,161.4,145.8,145.5,143.6,137.9,137.6,132.9,130.2,130.0,128.5,128.4,128.2,127.0,126.6,126.1,123.8,122.0,109.2,22.1,21.6.HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 16 NaO2323.1043;Found323.1037.

[0114] 6-Fluoro-3-hydroxy-2-(m-tolyl)-9H-fluoren-9-one(3kk)

[0115] 1 H NMR(400 MHz,DMSO-d6):δ10.96(br s,1H),7.64(dd,J1=8.8 Hz,J2=2.4 Hz,1H),7.60(dd,J1=8.0 Hz,J2=5.2 Hz,1H),7.47(s,1H),7.37-7.35(m,2H),7.31(t,J=7.6Hz,1H),7.27(s,1H),7.18-7.13(m,2H),2.36(s,3H). 13 C NMR(100 MHz,DMSO-d6):δ190.4,167.0(d, 1 J C-F =250.7 Hz),161.7,146.5(d,3 J C-F =10.9 Hz),144.1(d, 4 J C-F =2.2 Hz),137.7,137.6,131.5(d, 4 J C-F =2.2 Hz),130.0,129.3,128.4,128.3,127.0,126.6,126.1,126.0,116.1(d, 2 J C-F =23.1 Hz),110.0,109.6(d, 2 J C-F =24.6 Hz),21.5. 19 F NMR(376MHz,DMSO-d6):δ-104.15–-104.18(m).HRMS(ESI)m / z:[M+Na] + Calcd forC 20 H 13 FNaO2327.0792;Found 327.0790.

[0116] 6-Chloro-3-hydroxy-2-(m-tolyl)-9H-fluoren-9-one(3ll)

[0117] 1 H NMR(600 MHz,DMSO-d6):δ11.03(br s,1H),7.85(d,J=1.8 Hz,1H),7.55(d,J=7.8 Hz,1H),7.48(s,1H),7.41(dd,J1=7.8 Hz,J2=1.2 Hz,1H),7.37-7.35(m,2H),7.32-7.30(m,2H),7.15(d,J=7.2 Hz,1H),2.36(s,3H). 13 C NMR(100 MHz,DMSO-d6):δ190.6,161.8,145.3,144.4,139.9,137.7,137.6,133.8,130.0,129.6,129.4,128.4,128.3,127.3,126.6,125.8,125.2,121.8,110.0,21.5.HRMS(ESI)m / z:[M+Na] + Calcd forC 20 H 13 ClNaO2343.0496;Found 343.0493.

[0118] 6-Bromo-3-hydroxy-2-(m-tolyl)-9H-fluoren-9-one(3mm)

[0119] 1 H NMR(600 MHz,DMSO-d6):δ11.01(br s,1H),8.00(d,J=1.2 Hz,1H),7.57(dd,J1=7.8 Hz,J2=1.2 Hz,1H),7.49-7.47(m,2H),7.37-7.35(m,2H),7.32-7.29(m,2H),7.15(d,J=7.2 Hz,1H),2.36(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ190.8,161.8,145.4,144.4,137.7,137.6,134.1,132.6,130.0,129.5,129.0,128.4,128.3,127.3,126.6,125.6,125.4,124.6,110.1,21.5.HRMS(ESI)m / z:[M+Na] + Calcd forC 20 H 13 BrNaO2386.9991;Found386.9990.

[0120] 3-Hydroxy-2-(m-tolyl)-6-(trifluoromethyl)-9H-fluoren-9-one(3nn)

[0121] 1 H NMR(600 MHz,DMSO-d6):δ11.12(br s,1H),8.10(s,1H),7.74-7.71(m,2H),7.52(s,1H),7.39-7.36(m,3H),7.31(t,J=7.2 Hz,1H),7.16(d,J=7.2 Hz,1H),2.36(s,3H). 13 C NMR(150 MHz,DMSO-d6):δ190.6,162.3,144.7,144.2,138.4,137.72,137.68,134.6(q, 2 J C-F =31.8 Hz),130.1,1129.8,128.5,128.4,127.6,127.2(q, 3 J C-F=3.3 Hz),126.7,125.6,124.33(q, 1 J C-F =271.4 Hz),124.28,118.3,110.4,21.6. 19 F NMR(565 MHz,DMSO-d6):δ-61.46(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 13 F3NaO2377.0760;Found377.0772.

[0122] 3-Hydroxy-2-(m-tolyl)-7-(trifluoromethyl)-9H-fluoren-9-one(3oo)

[0123] 1 H NMR(600 MHz,DMSO-d6):δ11.11(br s,1H),7.96(d,J=7.8 Hz,1H),7.93(d,J=7.8 Hz,1H),7.79(s,1H),7.55(s,1H),7.38-7.36(m,3H),7.31(t,J=7.8 Hz,1H),7.17(d,J=7.2 Hz,1H),2.36(s,3H).. 13 C NMR(150 MHz,DMSO-d6):δ190.2,162.1,146.9,144.3,137.7,137.5,135.9,132.2(q, 3 J C-F =4.4 Hz),130.1(q, 2 J C-F =31.8 Hz),130.04,129.97,128.5,128.4,127.6,126.6,125.9,124.3(q, 1 J C-F =270.2Hz),122.1,120.1(q, 3 J C-F =3.3 Hz),110.3,21.5. 19 F NMR(565 MHz,DMSO-d6):δ-61.20(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 21 H 13 F3NaO2377.0760;Found377.0759.

[0124] 1-Chloro-6-hydroxy-7-(m-tolyl)-9H-fluoren-9-one(3pp)

[0125] 1 H NMR(400 MHz,DMSO-d6):δ10.89(br s,1H),7.70(d,J=7.2 Hz,1H),7.60-7.56(m,2H),7.48(s,1H),7.40-7.36(m,2H),7.31(t,J=7.2 Hz,1H),7.25(s,1H),7.15(d,J=7.2 Hz,1H),2.36(s,3H). 13 C NMR(100 MHz,DMSO-d6):δ192.0,161.7,145.7,143.2,137.8,137.6,135.2,135.1,130.01,129.96,128.7,128.4,128.2,127.2,126.6,125.6,123.8,121.3,109.3,21.6.HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 13 ClNaO2343.0496;Found343.0498.

[0126] 9-Hydroxy-8-(m-tolyl)-6H-fluoreno[3,4-d][1,3]dioxol-6-one(3qq)

[0127] 1 H NMR(600MHz,DMSO-d6):δ10.81(br s,1H),7.46(s,1H),7.38-7.36(m,2H),7.30(t,J=7.2Hz,1H),7.18-7.14(m,3H),6.83(d,J=7.8Hz,1H),6.28(s,2H),2.36(s,3H). 13 CNMR(150MHz,DMSO-d6):δ189.8,161.3,154.1,142.1,141.9,137.8,137.6,130.2,130.0,128.4,128.2,127.0,126.6,126.4,122.1,119.7,111.3,107.9,103.5,21.5.HRMS(ESI)m / z:[M+Na] + Calcd for C21 H 14 NaO4353.0784; Found 353.0787.

[0128] Example 4

[0129] The product 3-hydroxyfluorenone compound 3 synthesized by the present invention is subjected to a series of reactions to synthesize further derivatives, thereby demonstrating its important application value in organic synthesis. For example:

[0130]

[0131] 3a (54.5 mg, 0.2 mmol), N,N'-dicyclohexylcarbodiimide (41.3 mg, 0.2 mmol), 4-dimethylaminopyridine (4.9 mg, 0.04 mmol) and ibuprofen (41.3 mg, 0.2 mmol) were added to the reaction tube in sequence, and dichloromethane (1 mL) was added to dissolve them. The reaction system was then reacted at room temperature for 24 h. After the reaction was completed, it was filtered through celite and washed with dichloromethane. The filtrate was concentrated and separated by silica gel column (petroleum ether / ethyl acetate = 6 / 1) to obtain a yellow solid product 4 (57.1 mg, 62%). 1 H NMR (600MHz, CDCl3): δ7.59 (s, 1H), 7.55 (d, J = 7.2Hz, 1H), 7.37-7.34 (m, 2H), 7.21-7.16 (m, 6H), 7.10 (s, 1H), 7.05-6.9 8(m,4H),3.68(q,J=7.2Hz,1H),2.39(d,J=7.2Hz,2H),1.82-1.75(m,1H),1.33(d,J=7.2Hz,3H),0.84(d,J=6.4Hz,6H). 13 C NMR (150MHz, CDCl3): δ192.6,172.7,153.0,144.8,143.3,140.9,136.5,136.4,135.6,134.8,134.6,132.0,129.53,129 .47,128.8,128.3,127.8,127.3,127.0,124.4,120.7,115.5,45.2,45.1,30.2,22.5,22.4,18.4.HRMS(ESI)m / z:[M+Na] + Calcd for C 32 H 28 NaO3483.1931; Found 483.1937.

[0132]

[0133] 3a (54.5 mg, 0.2 mmol), N,N'-dicyclohexylcarbodiimide (41.3 mg, 0.2 mmol), 4-dimethylaminopyridine (4.9 mg, 0.04 mmol), and oxaprozin (58.7 mg, 0.2 mmol) were added to a reaction tube in sequence, and then dissolved in dichloromethane (1 mL). The reaction tube was then left to react at room temperature for 24 hours. After the reaction was complete, the mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1) to obtain the product 5 (68.3 mg, 63%) as a yellow solid. 1 H NMR (600MHz, CDCl3): δ8.60(d,J=4.2Hz,1H),7.72(s,1H),7.66(d,J=7.2Hz,1H),7.48(td,J1=7.8Hz,J2=1.2Hz,1H),7 .39-7.36(m,4H),7.33-7.30(m,3H),7.27-7.24(m,1H),7.09-7.06(m,2H),7.00(d,J=7.2Hz,1H),4.05-4.01(m,1H),3. 95-3.91(m,1H),3.10(dd,J1=16.8Hz,J2=1.2Hz,1H),2.97(dd,J1=16.8Hz,J2=2.4Hz,1H),2.86-2.81(m,1H),2.79-2.7 2(m,3H),1.99-1.95(m,1H),1.84-1.80(m,1H),1.27(td,J1=7.8Hz,J2=1.8Hz,3H),0.70(td,J1=7.2Hz,J2=2.4Hz,3H). 13 C NMR (150MHz, CDCl3): δ192.5,170.9,152.5,145.1,143.2,136.3,125.8,135.1,134..9,134.57,134.55,132.5,129.7,128.6,128.2,1 27.0,126.6,126.1,124.5,120.8,120.6,119.8,116.1,115.4,108.9,60.7,43.1,30.7,24.1,22.4,13.7,7.51.HRMS(ESI)m / z:[M+Na] + Calcd for C 36 H 31 NNaO4564.2145; Found 564.2147.

[0134]

[0135] To a reaction tube, 3a (54.5 mg, 0.2 mmol), 4-dimethylaminopyridine (110.0 mg, 0.9 mmol), trifluoromethanesulfonic anhydride (75.8 mg, 0.45 mmol), and DCM (2 mL) were added sequentially. The reaction flask was then left to react at room temperature for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was filtered through a silica gel column (petroleum ether / ethyl acetate = 6 / 1) to afford the product 6 (56.6 mg, 70%) as a yellow solid. 1 HNMR (600MHz, CDCl3): δ7.78 (s, 1H), 7.72 (d, J = 7.2Hz, 1H), 7.60-7.56 (m, 2H), 7.51 (s, 1H), 7.49-7.43 (m, 5H), 7.39 (td, J1 = 7.2Hz, J2 = 1.2Hz, 1H). 13 C NMR (150MHz, CDCl3): δ191.8,150.7,145.2,142.5,136.1,135.3,134.7,134.3,133.6,130.2,129.2,128.9,128.7,127.7,124.8,121.1,114.6. 19 F NMR(565MHz,CDCl3):δ-73.87(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 11 F3NaO4S 427.0222; Found 427.0225.

[0136]

[0137] To a reaction tube were added 6 (40.4 mg, 0.1 mmol), diphenylacetylene (19.6 mg, 0.11 mmol), palladium acetate (1.0 mg, 0.005 mmol), dppp (3.0 mg, 0.11 mmol), diethylamine (14.6 mg, 0.2 mmol), and N,N-dimethylformamide (1 mL). The tube was then sealed and the mixture was stirred in an oil bath at 110°C in air for 16 hours. After completion, the mixture was diluted with dichloromethane, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1) to yield 7 (23.4 mg, 27%) as a white solid. 1HNMR (600MHz, CDCl3): δ9.13(s,1H),8.83(d,J=8.4Hz,1H),7.73(d,J=7.2Hz,1H),7.72-7.69(m,1H),7.61(s,1H),7.5 5(d,J=7.8Hz,1H),7.50(t,J=7.2Hz,1H),7.44-7.43(m,2H),7.31-7.27(m,4H),7.25-7.20(m,3H),7.18-7.14(m,4H). 13 C NMR (150MHz, CDCl3): δ193.7,144.8,140.6,140.1,139.1,137.7,136.3,135.9,134.9,132.5,132.1,131.2,131.1,130.7, 130.6,129.2,128.2,127.8,127.7,127.3,127.2,126.9,126.8,124.4,122.8,121.0,119.8,119.1.HRMS(ESI)m / z:[M+Na] + Calcd for C 33 H 20 NaO 455.1406; Found 455.1410.

[0138] Example 5

[0139] The anticancer activity of the compounds was evaluated by studying the antiproliferative activity of cells using CCK8 analysis. First, cells were seeded into 96-well plates at a density of 5,000 cells per well with 100 μL of culture medium per well and incubated overnight at 37°C and 5% CO2. The next day, 100 μL of the test compound diluted with culture medium at different concentrations was added to each well, and then the cells were incubated at 37°C and 5% CO2 for 72 hours. Then, 10 μL of CCK8 was added to each well, and the 96-well plate was incubated at 37°C for 2 hours. The absorbance at 450 nm was measured using a multifunctional microplate reader (Perkin Elmer), and the IC was calculated using GraphPad Prism 6.0 software. 50 All experiments were performed in triplicate and repeated three times. A-549, HCT-116, and HeLa cancer cells were selected as the study subjects, and 5-fluorouracil (5-FU) was used as the positive control.

[0140] The anticancer activity results of some compounds are as follows:

[0141]

[0142] The activity results showed that the 3-hydroxyfluorenone compound 3 provided by the present invention was able to inhibit the proliferation of three cancer cells: A-549, HCT-116, and Hela. Among them, 3f, 3j, 3m, 3w, 3aa, 3ee, 3jj, and 3mm all showed significant antiproliferative effects on all three cancer cells. Compound 3g significantly inhibited the proliferation of both HCT-116 and Hela cancer cells, while 3s showed specific antiproliferative activity against Hela cancer cells, and 3v and 3cc showed specific antiproliferative activity against HCT-116 cancer cells. These activity results suggest that this class of compounds has medicinal value for preventing / treating / inhibiting the progression of cancer, particularly lung cancer, colon cancer, and cervical cancer.

[0143] The above embodiments illustrate the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and improvements may be made to the present invention without departing from the scope of the principles of the present invention, and all such changes and improvements fall within the scope of protection of the present invention.

Claims

1. 3-Hydroxyfluorenone compounds, the general structural formula of which is as follows: in: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, trifluoromethyl, phenyl, C 1-4 Alkoxycarbonyl, cyano or methylenedioxy, R 1 is a mono- or di-substituted, or R 1 Together with the benzene ring, it forms a naphthyl group; R 2 is selected from phenyl or substituted phenyl, the substituent on the substituted phenyl is a mono- or di-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen.

2. The 3-hydroxyfluorenone compound according to claim 1, characterized in that The specific structure is as follows:

3. Use of the 3-hydroxyfluorenone compound according to claim 1 or 2 in the preparation of anticancer drugs.

4. Use of the 3-hydroxyfluorenone compound according to claim 3 in the preparation of an anticancer drug, wherein the anticancer drug is lung cancer, colon cancer and / or cervical cancer.

5. A pharmaceutical composition for treating lung cancer, colon cancer and / or cervical cancer, wherein the active ingredient comprises the 3-hydroxyfluorenone compound according to claim 1 or 2.

6. The method for synthesizing 3-hydroxyfluorenone compounds according to claim 1, wherein: The method comprises the following steps: mixing an enaminone compound 1, a 1-substituted cyclopropanol compound 2, a catalyst, an additive and an organic solvent, and heating the mixture to react to obtain a 3-hydroxyfluorenone compound 3. The reaction equation is: Where: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogen, trifluoromethyl, phenyl, C 1-4 Alkoxycarbonyl, cyano or methylenedioxy, R 1 is a mono- or di-substituted, or R 1 Together with the benzene ring, it forms a naphthyl group; R 2 is phenyl or substituted phenyl, the substituent on the substituted phenyl is a mono- or di-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen.

7. The method for synthesizing 3-hydroxyfluorenone compounds according to claim 6, characterized in that: The catalyst is selected from [RhCp*Cl2]2 or [RhCp*(MeCN)3](SbF6)2; the additive is selected from a mixture of silver hexafluoroantimonate and copper acetate, a mixture of silver hexafluoroantimonate and copper acetate monohydrate, or a mixture of silver hexafluoroantimonate and silver acetate.

8. The method for synthesizing 3-hydroxyfluorenone compounds according to claim 6, characterized in that: The molar ratio of the enaminone compound 1, the 1-substituted cyclopropanol compound 2, the catalyst and the additive is 1:1-2:0.03-0.05:0.5-2.

5.

9. The method for synthesizing 3-hydroxyfluorenone compounds according to claim 6, characterized in that: The organic solvent is selected from methanol, ethanol or tetrahydrofuran; and the temperature of the reaction is selected from 60-110°C.

10. The method for synthesizing 3-hydroxyfluorenone compounds according to claim 6, characterized in that: The reaction is carried out in air or an inert gas atmosphere.

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