A phenanthridone derivative and a method for synthesizing the same

Abstract

The application discloses a phenanthridine ketone derivative which is composed of aromatic carboxylic acid, o-halogenated aniline, ruthenium catalyst, ligand, alkaline compound, additive and organic solvent, and a structural formula is shown as follows, wherein Ar 1 comprises various alkyl, aryl, trifluoromethyl, methoxy, thiomethyl, acetyl, fluorine, chlorine or bromine substituted groups; Ar 2 comprises various alkyl, trifluoromethyl, fluorine, chlorine, bromine substituted groups; R comprises alkyl, aryl or hydrogen; the application further discloses a synthesis method of the phenanthridine ketone derivative. The method of the application takes aromatic carboxylic acid and o-halogenated aniline as raw materials, takes commercially available metal ruthenium as a catalyst, and takes phosphine compound as a ligand, and the product has the characteristics of extremely high regioselectivity, wide substrate applicability, and the like, the raw materials / catalyst are cheap and easy to obtain, the operation is simple, the atomic economy is high, and the yield is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a phenanthrene ketone derivative and its synthesis method. Background Technology

[0002] Phenyridones are important structural units widely found in various natural products and bioactive drug molecules. Bioactive phenyridone derivatives are shown below:

[0003]

[0004] The bioactivity of phenanthrone skeletons manifests in antiviral, anticancer therapies, aurora kinase, and PARP inhibitory activities. For example, phenaglydon and crinasiadine are common natural products found in Amaryllidaceae plants and possess anti-inflammatory and anticancer effects (Org. Lett. 2017, 19, 1764-1767). PJ-34 has been shown to be a cell-permeable PARP inhibitor (Bioorg. Med. Chem. 2005, 13, 1151-1157). ARC-111 showed Top1 targeting activity and significant antitumor activity (J. Med. Chem. 2005, 48, 792-804). Fantridone has shown association with some DNA-related cytotoxicity (Eur. J. Med. Chem. 2011, 46, 2117e2131). Therefore, developing an efficient and atom-economical method to construct such molecular skeletons is highly attractive to chemists.

[0005] Currently, there are many methods for synthesizing phenanthrone derivatives. The most traditional method involves the Suzuki coupling of o-halobenzoic acid esters and o-aminophenylboronic acid (Tetrahedron 2006, 62, 5862-5867; Tetrahedron Lett. 2013, 54, 3712-3714). However, this method has significant drawbacks, such as the need for pre-prepared starting materials and low yield. Alternatively, phenanthrone compounds can be prepared by carbon-carbon coupling of pre-prepared aryl-substituted amides under transition metal catalysis or via a radical pathway (Chem. Sci. 2010, 1, 331-336; J. Am. Chem. Soc. 2006, 128, 581-590). In recent decades, methods for constructing phenanthrones using directed C-H bond activation strategies have developed rapidly. For example, amine-directed ortho-C-H bond activation for CO insertion (Chem. Commun. 2013, 49, 173-175; Org. Lett. 2013, 15, 1468-1471), amide-directed ortho-arylation (Angew. Chem. Int. Ed. 2011, 50, 1380-1383; Angew. Chem. Int. Ed. 2012, 51, 12343-12347), or insertion of benzyne (J. Org. Chem. 2012, 77, 8648-8656) can all yield phenanthrene derivatives relatively well. However, the raw materials used in these methods need to be prepared in advance, resulting in poor atom economy. Therefore, finding a simple and efficient method to prepare phenanthrene is very important. Summary of the Invention

[0006] In order to overcome the shortcomings of the existing technology, the present invention aims to provide a method for synthesizing phenanthrone derivatives, which solves the problem of poor atom economy and allows for the one-step construction of pharmaceutically valuable phenanthrone derivatives using commercially available starting materials.

[0007] Another object of the present invention is to provide a phenanthrene derivative.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] A method for synthesizing a phenanthrene derivative, the specific steps of which are as follows:

[0010] Under a protective atmosphere, aromatic carboxylic acid, o-haloaniline, ruthenium catalyst, ligand, basic compound, additive and organic solvent are added sequentially to the reaction vessel; the reaction is carried out at 100°C for 1 to 24 hours to obtain a reaction solution, and the reaction solution is further processed to obtain phenanthrene derivatives.

[0011] The molar ratio of the aromatic carboxylic acid to the o-haloaniline is 1:1 to 2;

[0012] The molar ratio of the ruthenium catalyst to the aromatic carboxylic acid is 0.01 to 0.05:1;

[0013] The molar ratio of the ligand to the aromatic carboxylic acid is 0.02 to 0.10:1.

[0014] Preferably, the protective atmosphere is nitrogen.

[0015] Preferably, the aromatic carboxylic acid is One or more of them;

[0016] Among them, R 1 Including one of methyl, ethyl, methoxy, thiomethyl, oxotrifluoromethyl, fluorine, chlorine, bromine or hydrogen;

[0017] R 2 Including one of methyl, phenyl, methoxy, trifluoromethyl, fluorine, or trifluoromethyl;

[0018] R 3 It includes one of methoxy or acetoxy.

[0019] Preferably, the ortho-haloaniline comprises One or more of them;

[0020] In each formula, X includes either bromine or iodine;

[0021] R 4 Includes one of methyl or fluorine;

[0022] R 5 Includes one of trifluoromethyl or fluorine;

[0023] R 6 It includes one of methyl, isopropyl, trifluoromethyl, fluorine, or chlorine.

[0024] Preferably, the ligand comprises tri-methylphosphine, tri-butylphosphine, tri-octylphosphine, tri-cyclohexylphosphine, diphenylmethylphosphine, triphenylphosphine, tri(4-trifluorotolyl)phosphine, tri(4-methoxyphenyl)phosphine, tri(pentafluorophenyl)phosphine, glycine, N-Boc-L-valine, L-tert-leucine, L-proline, diadamantyl-n-butylphosphine, dicyclohexyl-phenylphosphine, [1,1'-biphenyl]-2-yldi-cyclohexylphosphine, tri(4-methoxyphenyl)phosphine, trifuranylphosphine, and piperazine. Pyridine-2-carboxylic acid, 5-(trifluoromethyl)pyridin-2-ol, bipyridine, 4,4-dimethoxybipyridine, 4,4-di-tert-butylbipyridine, 4,4-dimethylbipyridine, 4,4-ditrifluoromethylbipyridine, 4,4-dicyanobipyridine, 6,6'-dimethyl-2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, methyl 2,2'-bipyridine-4,4'-dicarboxylate, 5,5'-dibromo-2,2'-bipyridine, [2,2'-bipyridine]- 6,6'(1H,1'H)-dione, 5-bromo-2,2'-bipyridine, 2,2'-bipyridine, 4,4'-diamino-2,2'-bipyridine, 1,10-phenanthroline, 2-bromo-1,10-phenanthroline, 1,10-phenanthroline-5,6-dione, 2,9-dimethyl-phenanthroline, 3,4,7,8-tetramethyl-1,10-phenanthroline, 4,7-diphenylphenanthroline, 4,7-dimethoxy-phenanthroline, (E)-N-benzyl-1-(pyridin-2-yl) One or more of the following: toluidine, (2E, 3E)-N2, N3-diphenylbutane-2,3-diimide, (2E, 3E)-N2, N3-diisopropylbutane-2,3-diimide, (2E, 3E)-N2, N3-bis(2,6-diisopropylphenyl)butane-2,3-diimide, N-benzylpyridine amide, N-(2-hydroxyethyl)pyridine amide, N,N'-(ethane-1,2-diacyl)diphenylsulfonamide, or [2,2'-bipyridine]-6,6'-diol.

[0025] Preferably, the ligand is tri-cyclohexylphosphine.

[0026] Preferably, the ruthenium catalyst comprises one or more of the following: tris(triphenylphosphine) dichloride ruthenium(II), di(triphenylphosphine)cyclopentadienyl ruthenium(II), bis-(2-methylallyl)cyclooctyl-1,5-diene ruthenium, chloro(pentamethylcyclopentadienyl)(cyclooctadiene) ruthenium(II), ruthenium trichloride, diiodo(p-cymene) ruthenium(II) dimer, or dichloro(p-cymene) ruthenium(II) dimer.

[0027] Preferably, the ruthenium catalyst is a diiodo(p-cymene)ruthenium(II) dimer.

[0028] Preferably, the alkaline compound includes one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium acetate, sodium acetate, cesium acetate, or potassium acetate.

[0029] Preferably, the alkaline compound is potassium phosphate or cesium carbonate.

[0030] Preferably, the additive includes one or more of the following: bis(trifluoromethanesulfonylimide)silver, silver hexafluoroantimonate, silver trifluoromethanesulfonate, silver tetrafluoroborate, adamantane carboxylic acid, adamantane acetic acid, potassium chloride, sodium chloride, lithium chloride, lithium bromide, or lithium phosphate.

[0031] Preferably, the additive is adamantane carboxylic acid.

[0032] Preferably, the organic solvent includes one or more of 1,4-dioxane, tetrahydrofuran, toluene, cyclohexane, 1,1,1,3,3,3-hexafluoro-2-propanol, trifluoroethanol, tert-butanol, acetonitrile, N-methylpyrrolidone, or N,N-dimethylformamide.

[0033] Preferably, the organic solvent is N-methylpyrrolidone.

[0034] Preferably, the subsequent processing includes one of a first subsequent processing and a second subsequent processing, and the specific steps of the first subsequent processing are as follows:

[0035] The reaction solution prepared above was sequentially cooled, pH value adjusted, extracted, solvent removed from the organic phase, and purified.

[0036] The specific steps of the second subsequent processing are as follows:

[0037] The reaction solution, iodomethane, and alkaline compound are mixed evenly and reacted at 60°C for 2-6 hours. Then, quenching reaction, extraction, removal of solvent from organic phase, and separation and purification are carried out sequentially.

[0038] The phenanthridine derivatives used in the first post-treatment are shown below:

[0039]

[0040] Preferably, the quenching reaction refers to the addition of a saturated sodium bicarbonate solution to the reaction system.

[0041] Preferably, the removal of solvent from the organic phase refers to the removal of water and organic solvent from the organic phase.

[0042] Preferably, the removal of water from the organic phase refers to drying with a desiccant followed by filtration.

[0043] Preferably, the desiccant is anhydrous magnesium sulfate.

[0044] Preferably, the removal of organic solvents from the organic phase refers to the removal of organic solvents by vacuum distillation.

[0045] Preferably, the separation and purification is performed using column chromatography, and the eluent for column chromatography includes a mixed solvent of petroleum ether and ethyl acetate or a mixed solvent of dichloromethane and ethyl acetate.

[0046] Preferably, the volume ratio of petroleum ether to ethyl acetate is 3-20:1.

[0047] Preferably, the ratio of dichloromethane to ethyl acetate is 5-20:1.

[0048] A phenanthridine ketone derivative, prepared according to the aforementioned synthetic method for a phenanthridine ketone derivative, has the following structural formula:

[0049]

[0050] Among them, Ar 1 Including one of the following groups: alkyl, aryl, trifluoromethyl, methoxy, thiomethyl, acetyl, fluorine, chlorine, or bromine-substituted groups;

[0051] Ar 2 Including one of the following groups: alkyl, trifluoromethyl, fluorine, chlorine, or bromine-substituted groups;

[0052] R includes one of alkyl, aryl, or hydrogen;

[0053] The present invention has the following advantages and beneficial effects compared with the prior art:

[0054] (1) In this invention, the carboxylic acid is first arylated at the ortho position, and then phenanthrene ketone is prepared by intramolecular dehydration. The ortho-haloaniline used in the reaction is a bifunctional reagent, serving as both an aryl electrophile and an intramolecular amine nucleophilic site. The use of a sterically hindered and electron-rich phosphine ligand not only solves the problem of the amino group in ortho-haloaniline inhibiting the intramolecular dehydration condensation between the weakly nucleophilic amino group and the carboxyl group, but also inhibits the poisoning of the amino group in ortho-haloaniline to the metal and the oxidative addition of the carboxylic acid cyclic ruthenium metal intermediate to ortho-haloaniline.

[0055] (2) The method disclosed in this invention uses aromatic carboxylic acids and o-haloaniline as raw materials, commercially available ruthenium metal as catalyst, and phosphine compound as ligand. The resulting product has wide substrate applicability, inexpensive and readily available raw materials / catalysts, and simple operation. It has the characteristics of high atom economy and high yield.

[0056] (3) The method disclosed in this invention can be used to construct phenaglydon containing drug molecules in one step, and the obtained phenaglydon skeleton can be further transformed to construct a series of complex phenaglydon derivatives.

[0057] (4) The reaction solution obtained in the synthesis process of some phenanthrene derivatives (e.g., Examples 1-8) has a high separation and purification efficiency when the first post-processing method is used; other reaction solutions have a low separation and purification efficiency when the first post-processing method is used. In this case, the second post-processing method is used to methylate them, which can improve the separation and purification efficiency. Attached Figure Description

[0058] Figure 1 Here are the chemical reaction equations for the synthesis method of this invention;

[0059] Figure 2 The 1H NMR spectrum of the phenanthrene derivative obtained in Example 1;

[0060] Figure 3 The 1H NMR spectrum of the phenanthrene derivative obtained in Example 2;

[0061] Figure 4 The 1H NMR spectrum of the phenanthrene derivative obtained in Example 3;

[0062] Figure 5 The 1H NMR spectrum of the phenanthrene derivative obtained in Example 4;

[0063] Figure 6 The 1H NMR spectrum of the phenanthrene derivative obtained in Example 5;

[0064] Figure 7 The 1H NMR spectrum of the phenanthrene derivative obtained in Example 6; Detailed Implementation

[0065] The invention's objective will be further described in detail below with reference to the accompanying drawings and specific embodiments. The embodiments cannot be described in detail here, but the implementation of the invention is not limited to the following embodiments.

[0066] Example 1

[0067] Under nitrogen protection, 0.3 mmol of 4-methylbenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 72% yield. The 1H NMR spectrum of the obtained phenanthrene derivative is shown below. Figure 2 As shown.

[0068] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.56(s,1H),8.34(d,J=7.9Hz,1H),8.28(s,1H),8.21(d,J= 8.1Hz,1H),7.52-7.40(m,2H),7.36(d,J=7.4Hz,1H),7.29-7.20(m,1H),2.52(s,3H); 13 C NMR (100MHz, DMSO) δ161.3,143.4,137.2,134.7,129.9,129.6,127.9,123.9,123.6,122.9,122.6,118.0,116.5,22.0.

[0069] Based on the above data, the structure of the obtained product can be inferred as follows:

[0070]

[0071] Example 2

[0072] Under nitrogen protection, 0.3 mmol of benzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantane carboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 91% yield. The 1H NMR spectrum of the obtained phenanthrene derivative is shown below. Figure 3 As shown.

[0073] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.68(s,1H),8.48(d,J=8.1Hz,1H),8.40-8.29(m,2H),7.84(t,J=7.7Hz ,1H),7.64(t,J=7.6Hz,1H),7.49(t,J=7.5Hz,1H),7.38(d,J=8.0Hz,1H),7.25(t,J=7.7Hz,1H); 13 C NMR (100MHz, DMSO-d6) δ161.3,137.0,134.7,133.2,130.0,128.4,127.9,126.2,123.7,123.0,122.7,118.0,116.6.

[0074] Based on the above data, the structure of the obtained product can be inferred as follows:

[0075]

[0076] Example 3

[0077] Under nitrogen protection, 0.3 mmol of 2-phenylbenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 77% yield. The 1H NMR spectrum of the obtained phenanthrene derivative is shown below. Figure 4 As shown.

[0078] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.32(s,1H),8.54(d,J=8.0Hz,1H),8.41(d,J=8.0Hz,1H), 7.82(t,J=7.8Hz,1H),7.48(t,J=7.5Hz,1H),7.41-7.30(m,5H),7.29-7.23(m,3H); 13 C NMR (100MHz, DMSO) δ 160.7, 144.7, 143.9, 137.3, 136.2, 132.1, 132.0, 130.1, 128.9, 127.6, 126.6, 124.1, 123.3, 122.7, 122.5, 118.0, 116.1. Based on the above data, the structure of the obtained product can be deduced as follows:

[0079]

[0080] Example 4

[0081] Under nitrogen protection, 0.3 mmol of 4-chlorobenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 81% yield. The 1H NMR spectrum of the obtained phenanthrene derivative is shown below. Figure 5 As shown.

[0082] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.58(s,1H),8.42(d,J=8.0Hz,1H),8.30(d,J=8.5Hz,1H), 7.66(dd,J=8.5,2.0Hz,1H),7.52(t,J=7.6Hz,1H),7.37(d,J=8.0Hz,1H),7.26(t,J=7.5Hz,1H); 13 C NMR (100MHz, DMSO) δ 160.7, 138.7, 137.5, 136.6, 130.8, 130.2, 128.5, 124.8, 124.3, 122.9, 122.9, 117.1, 116.7. Based on the above data, the structure of the obtained product can be deduced as follows:

[0083]

[0084] Example 5

[0085] Under nitrogen protection, 0.3 mmol of 2-methyl-4-methoxybenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 87% yield. The 1H NMR spectrum of the obtained phenanthrene derivative is shown below. Figure 6 As shown.

[0086] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),8.35(d,J=8.1Hz,1H),7.75(d,J=2.6Hz,1H),7.47-7.40 (m,1H),7.32-7.27(m,1H),7.22-7.15(m,1H),6.98(d,J=1.8Hz,1H),3.95(s,3H),2.82(s,3H); 13 C NMR (100MHz, DMSO-d6) δ162.2,161.9,144.1,138.5,137.5,130.0,124.3,122.1,119.3,118.1,118.1,115.8,104.0,56.0,24.4.

[0087] Based on the above data, the structure of the obtained product can be inferred as follows:

[0088]

[0089] Example 6

[0090] Under nitrogen protection, 0.3 mmol of 2-fluoro-3-methoxybenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 73% yield. The 1H NMR spectrum of the obtained phenanthrene derivative is shown below. Figure 7 As shown.

[0091] The structural characterization data of the obtained product are as follows: 1 H NMR(400MHz, DMSO-d6)δ11.50(s,1H),8.20(dd,J=8.6,5.2Hz,2H),7.63(t,J=8.5Hz, 1H),7.40(t,J=7.6Hz,1H),7.28(d,J=8.1Hz,1H),7.18(t,J=7.6Hz,1H),3.94(s,3H); 13 C NMR (100MHz, DMSO-d6) δ 158.8, 152.6, 150.0, 147.2, 147.1, 136.3, 129.4, 128.8, 123.4, 122.7, 119.2, 119.0, 119.0, 117.3, 116.1, 115.6, 56.9; Based on the above data, the structure of the obtained product is deduced as follows:

[0092]

[0093] Example 7

[0094] Under nitrogen protection, 0.3 mmol of 4-methylbenzoic acid, 0.45 mmol of 2-iodo-4-methylaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 80% yield.

[0095] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.48(s,1H),8.24(s,1H),8.19(d,J=8.1Hz,1H),8.13(s,1H),7.40(d,J=8.1Hz,1H),7.25(s,2H),2.50(s,3H),2.39(s,3H); 13 CNMR(100MHz,DMSO-d6)δ161.2,143.2,135.1,134.7,131.5,130.8,129.4,127.9,124.0,123.4,122.8,117.8,116.4,22.0,21.1.

[0096] Based on the above data, the structure of the obtained product can be inferred as follows:

[0097]

[0098] Example 8

[0099] Under nitrogen protection, 0.3 mmol of 4-methylbenzoic acid, 0.45 mmol of 2-iodo-4-chloroaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 20:1 (v / v) mixture of dichloromethane and ethyl acetate to yield the target product in 77% yield.

[0100] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.40(d,J=8.1Hz,1H),8.15(d,J=2.4Hz,1H),7.92(s,1H),7.48-7.40(m,2H),7.32-7.25(m,1H),3.76(s,3H),2.57(s,3H); 13 C NMR (100MHz, CDCl3) δ161.2,143.2,136.6,132.2,130.0,129.1,128.9,128.0,123.4,122.8,121.6,120.5,116.3,29.9,22.1.

[0101] Based on the above data, the structure of the obtained product can be inferred as follows:

[0102]

[0103] Example 9

[0104] Under nitrogen protection, 0.3 mmol of 4-methylbenzoic acid, 0.45 mmol of 2-bromo-N-phenylaniline, 0.012 mmol of diiodide (p-cymene)ruthenium(II) dimer, 0.024 mmol of trioctylphosphine, 0.048 mmol of adamantanecarboxylic acid, 0.3 mmol of cesium carbonate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to yield the target product in 78% yield.

[0105] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.49(d,J=8.1Hz,1H),8.31(dd,J=7.5,2.0Hz,1H),8.14(s,1H),7.64(t,J=7.5Hz,2H),7.5 6(t,J=7.4Hz,1H),7.46(d,J=8.1Hz,1H),7.40-7.35(m,2H),7.33-7.28(m,2H),6.78-6.67(m,1H),2.62(s,3H); 13C NMR (100MHz, CDCl3) δ161.6,143.2,139.2,138.3,133.9,130.0,129.4,12 9.1,128.9,128.8,128.6,123.5,122.8,122.4,121.7,118.9,116.9,22.1.

[0106] Based on the above data, the structure of the obtained product can be inferred as follows:

[0107]

[0108] Example 10

[0109] Under nitrogen protection, 0.3 mmol of 4-methylbenzoic acid, 0.45 mmol of 2-bromo-N-methylaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of trioctylphosphine, 0.048 mmol of adamantanecarboxylic acid, 0.3 mmol of cesium carbonate, and 2 mL of N-methylpyrrolidone were added sequentially to a reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. The reaction solution was washed with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to yield the target product in 73% yield.

[0110] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.37(d,J=8.1Hz,1H),8.12(d,J=7.8Hz,1H),7.91(s,1H),7.45(t,J=7.7Hz, 1H),7.33(d,J=8.1Hz,1H),7.28(d,J=8.3Hz,1H),7.22(t,J=7.2Hz,1H),3.71(s,1H),2.50(s,2H); 13 C NMR (100MHz, CDCl3) δ161.3,142.5,137.8,133.2,129.1,129.0,128.5,123.0,122.8,122.0,121.4,118.9,114.7,29.6,21.9.

[0111] Based on the above data, the structure of the obtained product can be inferred as follows:

[0112]

[0113] Example 11

[0114] Under nitrogen protection, 0.3 mmol of 4-methylbenzoic acid, 0.45 mmol of 2-bromo-4,6-difluoroaniline, 0.012 mmol of diiodide (p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.048 mmol of adamantanecarboxylic acid, 0.3 mmol of cesium carbonate, and 2 mL of N-methylpyrrolidone were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate water and extracted with ethyl acetate. The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The solution was then purified by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 5:1 to obtain the target product in a yield of 63%.

[0115] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.35(d,J=8.1Hz,1H),7.78(s,1H),7.62(d,J=9.4Hz,1H),7.40(d ,J=8.2Hz,1H),6.97(ddd,J=14.2,7.9,2.8Hz,1H),3.87(d,J=9.6Hz,3H),2.52(s,3H); 13 C NMR(100MHz,CDCl3)δ161.7,157.3(dd,J C-F =7.0,242.0Hz),151.0(dd,J C-F =12.0,247.0Hz),143.3,132.1(t,J C-F =3.0Hz),130.6,129.0,124.2(dd,J C-F =3.0,6.0Hz),123.6,122.8(dd,J C-F =4.0,9.0Hz),122.0,105.5(t,J) C-F =27.0Hz), 105.0(dd,J C-F =4.0, 23.0 Hz), 34.0 (d, J) C-F =16.0Hz), 22.1. Based on the above data, infer the structure of the obtained product:

[0116]

[0117] Example 12

[0118] Under nitrogen protection, 0.3 mmol of 2,4-dimethylbenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 85% yield.

[0119] The structural characterization data of the obtained product are as follows: 1 H NMR(500MHz, CDCl3)δ8.24(dd,J=8.1,1.4Hz,1H),7.94(s,1H),7.49(ddd,J=8.5,7.2,1.4Hz,1H ),7.33(d,J=8.4Hz,1H),7.29-7.24(m,1H),7.18(s,1H),3.73(s,3H),2.93(s,3H),2.49(s,3H); 13 C NMR (125MHz, CDCl3) δ162.4,142.4,141.7,138.3,135.1,133.1,129.3,123.5,121.9,121.8,120.0,119.4,114.6,29.6,24.5,21.8.

[0120] Based on the above data, the structure of the obtained product can be inferred as follows:

[0121]

[0122] Example 13

[0123] Under nitrogen protection, 0.3 mmol of 2-methyl-4-chlorobenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 54% yield.

[0124] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.37(d,J=8.0Hz,1H),7.87(s,1H),7.72(s,1H),7.4 3(t,J=7.5Hz,1H),7.34(d,J=7.8Hz,1H),7.23(t,J=7.5Hz,1H),4.02(s,3H),3.91(s,3H); 13 C NMR (100MHz, DMSO) δ160.9,153.7,149.9,136.5,129.5,129.0,123.6,122.3,119.8,118.1,116.4,108.3,104.5,56.6,56.0.

[0125] Based on the above data, the structure of the obtained product can be inferred as follows:

[0126]

[0127] Example 14

[0128] Under nitrogen protection, 0.3 mmol of 2-methyl-4-bromobenzoic acid, 0.45 mmol of 2-iodoaniline, 0.012 mmol of diiodo(p-cymene)ruthenium(II) dimer, 0.024 mmol of tricyclohexylphosphine, 0.024 mmol of adamantanecarboxylic acid, 0.45 mmol of potassium phosphate, and 2 mL of N-methylpyrrolidone were added sequentially to the reaction vessel. The mixture was stirred at 100 °C for 24 h, then heating and stirring were stopped, and the mixture was cooled to room temperature. Then, 3.0 mmol of iodomethane and 0.6 mmol of potassium carbonate were added again, and the mixture was stirred at 60 °C for 2 h. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by vacuum distillation. The product was then purified by column chromatography using a 5:1 (v / v) mixture of petroleum ether and ethyl acetate to obtain the target product in 46% yield.

[0129] The structural characterization data of the obtained product are as follows: 1 H NMR (400MHz, CDCl3) δ8.20(d,J=2.0Hz,1H),8.10(d,J=9.1Hz,1H),7.53(ddd,J=8.5,7.2,1.5Hz,1H),7.45 (dd,J=1.9,0.9Hz,1H),7.32(d,J=8.1Hz,1H),7.26(ddd,J=8.2,7.3,1.3Hz,1H),3.70(s,3H),2.91(s,3H); 13 CNMR (100MHz, CDCl3) δ161.7,144.7,138.2,136.5,134.1,130.1,126.5,123.6,122.8,122.7,122.2,118.1,114.6,29.7,24.5.

[0130] Based on the above data, the structure of the obtained product can be inferred as follows:

[0131]

[0132] The above-described specific embodiments are preferred embodiments of the present invention and are not intended to limit the present invention. Any other changes or equivalent substitutions made without departing from the technical solution of the present invention are included within the protection scope of the present invention.

Claims

1. A method for synthesizing a phenanthridine ketone derivative, characterized in that, The specific steps are as follows: Under a protective atmosphere, aromatic carboxylic acid 1, o-haloaniline 2, ruthenium catalyst, ligand, basic compound, additive and organic solvent were added sequentially to the reaction vessel; the reaction was carried out at 80~140℃ for 1~24h to obtain a reaction solution, and after further processing, phenanthrene ketone derivative 3 was obtained. The chemical reaction equations for the synthesis method are as follows: ； The subsequent processing includes one of a first subsequent processing and a second subsequent processing. The specific steps of the first subsequent processing are as follows: The reaction solution prepared above was sequentially cooled, pH adjusted, extracted, solvent removed from the organic phase, and purified. The structure of the phenanthridine derivative 3 obtained by the first subsequent treatment is as follows: , , , , , , , , , , , , , ; The specific steps of the second subsequent processing are as follows: The reaction solution, iodomethane, and alkaline compound are mixed evenly and reacted at 60°C for 2-6 hours. Then, quenching reaction, extraction, removal of solvent from organic phase, and separation and purification are carried out sequentially. The structure of the phenanthridine derivative 3 obtained by the second subsequent processing is as follows: , , , ; The molar ratio of the aromatic carboxylic acid 1 to the o-haloaniline 2 is 1:1~2; The molar ratio of the ruthenium catalyst to the aromatic carboxylic acid 1 is 0.01~0.05:1; The molar ratio of the ligand to the aromatic carboxylic acid 1 is 0.02~0.10:1; The ligand is tri-methylphosphine, tri-butylphosphine, tri-octylphosphine or tri-cyclohexylphosphine; The ruthenium catalyst is a diiodine (p-cymene)ruthenium(II) dimer or a dichloro (p-cymene)ruthenium(II) dimer; The additive is adamantane carboxylic acid or adamantane acetic acid.

2. The method for synthesizing a phenanthrene derivative according to claim 1, characterized in that, The alkaline compound is one or more of potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, dipotassium hydrogen phosphate, potassium bicarbonate, sodium bicarbonate, lithium acetate, sodium acetate, cesium acetate, or potassium acetate.

3. The method for synthesizing a phenanthrene derivative according to claim 1, characterized in that, The organic solvent is one or more of 1,4-dioxane, tetrahydrofuran, toluene, cyclohexane, 1,1,1,3,3,3-hexafluoro-2-propanol, trifluoroethanol, tert-butanol, acetonitrile, N-methylpyrrolidone, or N,N-dimethylformamide.

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