Phosphine-containing pyridino-phenanthridine ketone derivative as well as electrochemical synthesis method and application thereof

Abstract

The invention belongs to the technical field of organic electrochemical synthesis, and particularly discloses a phosphine-containing pyridino-phenanthridine ketone derivative as well as an electrochemical synthesis method and application of the phosphine-containing pyridino-phenanthridine ketone derivative. The preparation method comprises the following steps: mixing an N-aryl acrylamide compound, a symmetric phosphonyl compound, an electrolyte, an additive, alkali and an organic solvent, and electrifying to react, so as to obtain the phosphine-containing pyridino-phenanthridine ketone derivative. According to the method, a metal catalyst is not needed, only the ferrocene oxidation substrate is catalyzed through electric induction circulation, a by-product is hydrogen, and the method has the advantages that raw materials are easy to obtain, operation is easy, electrolyte and a solvent can be used mechanically, and the method has high implementation value and social and economic benefits. The synthesized compound has an inhibition effect on proliferation of breast cancer cells. Experimental results show that a plurality of compound examples show remarkable anti-proliferative activity on the tumor cell line under low micromolar concentration, important candidate molecules are provided for developing novel anti-tumor drugs, and potential clinical application value is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic electrochemical synthesis, and in particular to a phosphine-containing pyridophenanthridinone derivative and an electrochemical synthesis method and application thereof. Background Art

[0002] The pyridophenanthridine ring is an important nitrogen-containing heterocyclic structure and the structural core of numerous natural alkaloids. Both natural and synthetic pyridophenanthridine derivatives exhibit a wide range of pharmacological and biological activities. The phenanthridine ring, in particular, possesses unique antibacterial, antiviral, anti-inflammatory, and antitumor activities. For example, chelerythrine, which contains the phenanthridine core, exhibits anti-cytotoxic and antibacterial activities; fagaronine has excellent anticancer activity; and lycorine has a potent emetic effect and shows great potential in clinical anti-tumor drug research.

[0003] Organophosphorus compounds, especially phosphorylated heterocyclic compounds, have received much attention in the fields of materials chemistry, pharmaceuticals, and agricultural chemistry. Therefore, in recent years, a large number of non-traditional synthetic methods for the synthesis of phosphorylated heterocycles have been reported. For example, in 2024, Zhuo Zhang et al. explored the use of photocatalytic energy level conversion to achieve molecular redox processes, generate phosphoryl radical intermediates through hydrogen atom transfer, and ultimately introduce the phosphinoyl radical into the pyrrolopyrimidine heterocycle to construct a CP bond (Asian J.Org.Chem.2024,13,e202400015). In 2023, Xiaocong Zhou et al. reported an electrochemically induced phosphinoyl radical formation and addition with methacrylamide compounds to construct a CP bond and synthesize a series of phosphoric acid-functionalized oxindoles (J.Org.Chem.2023,88,17521-17526).

[0004] Compared with the phosphonylation synthesis that has taken the lead in the field of green chemical synthesis, the synthesis of pyridophenanthridine compounds in recent years is still mainly concentrated on the following routes: traditional oxidant synthesis of pyridophenanthridine derivatives, transition metal-catalyzed cyclization, isocyanate radical cyclization and other methods. Among them, the representative ones are: In 2020, Lei Ji et al. reported an iron-mediated deuterium addition cascade cyano insertion / cyclization reaction, using N-aryl acrylamide and sodium deuterated borohydride (NaBD4) as raw materials, under the catalysis of Fe(NO3)3·9H2O, through a free radical pathway, the deuterium radical first adds to the olefin, then undergoes cyano insertion and cyclization steps, and finally forms the deuterated pyridophenanthridine product (Org Biomol Chem. 2020, 18(31), 6126-6133). In 2024, Cui Zhang et al. reported a cascade cyclization reaction of aldehydes with N-(o-cyanobiaryl)acrylamide, and in the DTBP / malonic acid or TBHP system, through the intramolecular addition of carbon-centered free radicals to the nitrile group and the cyclization of the aromatic ring by imine radicals, three new chemical bonds and two new rings were constructed in one step to synthesize alkyl and carbonyl substituted pyridophenanthridine compounds (Adv. Synth. Catal. 2024, 366, 2835-2841). In the same year, Bo Jiang's team reported a method for synthesizing azide-substituted pyridophenanthridine compounds through the oxidative cascade cyclization reaction of N-(o-cyanobiaryl)acrylamide with TMSN3. Using diethyl oxalate as solvent, the reaction was triggered by azide radicals to construct two C–N bonds and one C–C bond in one step, and finally terminated with intramolecular cyclization of the nitrile group and final ring closure of the aromatic ring (Org Biomol Chem. 2024, 22, 1186-1193).

[0005] Most of these methods have shortcomings, such as the use of metal catalysts, expensive inducers, harsh reaction conditions, and large amounts of three wastes.

[0006] Over the past few decades, electrochemical synthesis has made considerable progress and has become a powerful tool for new drug development. To date, few studies have reported on the construction of phosphine-containing functional groups into pyridophenanthridine rings using green electrochemical strategies. Summary of the Invention

[0007] In view of this, the present invention provides a phosphine-containing pyridophenanthridinone derivative and its electrochemical synthesis method and application, in order to solve the problems of the existing preparation method of pyridophenanthridine compounds, such as the need to use metal catalysts, expensive inducers, harsh reaction conditions, and large amounts of three wastes, as well as the problem that there are few reports on the construction of phosphine-containing functional groups into the pyridophenanthridine ring.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] A phosphine-containing pyridophenanthridinone derivative, wherein the structure of the phosphine-containing pyridophenanthridinone derivative is as follows:

[0010]

[0011] Among them, R 1 is hydrogen, alkyl, halogen, alkoxy, sulfonyl, trifluoromethyl, or naphthalene ring;

[0012] R 2 Ethyl;

[0013] R 3 It is a benzene ring, cyclohexane or a substituted benzene ring.

[0014] Another object of the present invention is to provide an electrochemical synthesis method of phosphine-containing pyridophenanthridinone derivatives, comprising the following steps:

[0015] An N-aryl acrylamide compound, a symmetrical phosphonyl compound, an additive, a base, an electrolyte and an organic solvent are mixed, and electricity is applied to react to obtain a phosphine-containing pyridophenanthridinone derivative;

[0016] The structural formula of the N-aryl acrylamide compound is:

[0017] Among them, R 1 is hydrogen, alkyl, halogen, alkoxy, sulfonyl, trifluoromethyl, or naphthalene ring;

[0018] R 2 Ethyl;

[0019] The structural formula of the symmetrical phosphono compound is:

[0020] R 3 It is a benzene ring, cyclohexane or a substituted benzene ring.

[0021] Preferably, the molar ratio of the N-aryl acrylamide compound, the symmetrical phosphonic acid compound, the electrolyte, the additive and the base is 1:1-5:1-5:0.2-1:0.2-2;

[0022] The molar volume ratio of the N-aryl acrylamide compound to the organic solvent is 1 mmol:10-20 mL.

[0023] Preferably, the reaction temperature is room temperature to 80° C.; the reaction time is 4 to 24 hours; and the reaction current is 3 to 8 mA.

[0024] Preferably, the electrolyte comprises one or more of tetrabutylammonium hexafluorophosphonate, tetrabutylammonium chloride, tetrabutylammonium acetate and tetrabutylammonium perchlorate;

[0025] The additive is ferrocene;

[0026] The base includes one or more of triethylamine, cesium carbonate, sodium carbonate, sodium bicarbonate and 1,4-dimethylaminopyridine;

[0027] The organic solvent includes one or more of acetonitrile, tetrahydrofuran, methanol and 1,4-dioxane.

[0028] Preferably, the energized positive electrode and negative electrode materials independently include graphite felt electrodes, carbon rod electrodes, platinum electrodes or nickel electrodes.

[0029] Another object of the present invention is to provide a use of a phosphine-containing pyridophenanthridinone derivative prepared by the above preparation method in the preparation of anti-tumor drugs.

[0030] It can be seen from the above technical solutions that compared with the prior art, the present invention has the following beneficial effects:

[0031] The method of the present invention does not require the use of metal catalysts, strong oxidants and other reagents. It only uses electric induction circulation to catalyze the oxidation of ferrocene as a substrate and electrocatalytic oxidative dehydrogenation. The by-product is hydrogen. At the same time, the reaction medium can be recycled and reused, and the emission of three wastes is almost zero. It is more green and environmentally friendly, and the raw materials are easily available, the operation is simple, and it is environmentally friendly. It also has the characteristics of high reaction efficiency and the like, and has great implementation value and social and economic benefits. DETAILED DESCRIPTION

[0032] The present invention provides a phosphine-containing pyridophenanthridinone derivative, the structure of the phosphine-containing pyridophenanthridinone derivative is as follows:

[0033]

[0034] In the present invention, R 1 is hydrogen, alkyl, halogen, alkoxy, sulfonyl, trifluoromethyl, or naphthalene ring; R 2 is ethyl; R 3 is a benzene ring, a cyclohexane ring or a substituted benzene ring, wherein the substituent of the substituted benzene ring includes an alkyl group, an alkoxy group or a halogen group.

[0035] The present invention also provides an electrochemical synthesis method of phosphine-containing pyridophenanthridinone derivatives, comprising the following steps:

[0036] An N-aryl acrylamide compound, a symmetrical phosphonyl compound, an electrolyte, an additive, a base and an organic solvent are mixed, and electricity is applied to react to obtain a phosphine-containing pyridophenanthridinone derivative.

[0037] In the present invention, the reaction equation is as follows:

[0038]

[0039] In the present invention, the structural formula of the N-aryl acrylamide compound is:

[0040]

[0041] Among them, R 1 is hydrogen, alkyl, halogen, alkoxy, sulfonyl, trifluoromethyl, or naphthalene ring; R 2 For ethyl.

[0042] In the present invention, the structural formula of the symmetrical phosphono compound is:

[0043] R 3 is a benzene ring, a cyclohexane ring or a substituted benzene ring, wherein the substituent of the substituted benzene ring includes an alkyl group, an alkoxy group or a halogen group.

[0044] In the present invention, the molar ratio of the N-aryl acrylamide compound, the symmetrical phosphonic acid compound, the electrolyte, the additive and the base is 1:1-5:1-5:0.2-1:0.2-2, preferably 1:2-4:2-4:0.5-0.8:0.5-1.5, and more preferably 1:3:3:0.6:1.

[0045] In the present invention, the molar volume ratio of the N-arylacrylamide compound to the organic solvent is 1 mmol:10-20 mL, preferably 1 mmol:12-18 mL, and more preferably 1 mmol:15 mL.

[0046] In the present invention, the reaction temperature is room temperature to 80°C, specifically 20°C, 30°C, 40°C, 50°C, 60°C, and 70°C; the reaction time is 4 to 24 hours, specifically 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, and 22 hours; the reaction current is 3 to 8 mA, specifically 4 mA, 5 mA, 6 mA, and 7 mA, preferably a constant current.

[0047] In the present invention, the electrolyte includes one or more of tetrabutylammonium hexafluorophosphonate, tetrabutylammonium chloride, tetrabutylammonium acetate and tetrabutylammonium perchlorate, preferably tetrabutylammonium hexafluorophosphonate; the additive is ferrocene; the base includes one or more of triethylamine, cesium carbonate, sodium carbonate, sodium bicarbonate and 1,4-dimethylaminopyridine, preferably triethylamine; the organic solvent includes one or more of acetonitrile, tetrahydrofuran, methanol and 1,4-dioxane, preferably acetonitrile / 1,4-dioxane, tetrahydrofuran / 1,4-dioxane, and more preferably acetonitrile / 1,4-dioxane.

[0048] In the present invention, the electrically conductive positive and negative electrodes are independently made of graphite felt, carbon rod, platinum, or nickel, with the nickel electrode comprising a nickel foam. The spacing between the positive and negative electrodes is preferably 0.5 to 1 cm, specifically 0.6 cm, 0.7 cm, 0.8 cm, or 0.9 cm.

[0049] The present invention also provides a use of the phosphine-containing pyridophenanthridinone derivative prepared by the above preparation method in the preparation of anti-tumor drugs.

[0050] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0051] Example 1

[0052] N-(2-cyano-[1,1'-biphenyl]-3-yl)-N-methylmethylacrylamide (132.7 mg, 0.5 mmol), diphenylphosphine oxide (252.7.0 mg, 1.25 mmol), ferrocene (46.5 mg, 0.25 mmol), triethylamine (50.6 mg, 0.5 mmol), tetrabutylammonium hexafluorophosphonate (484.3 mg, 1.25 mmol), acetonitrile (3 mL) and 1,4-dioxane (3 mL) were added to a reaction tube, and a graphite felt electrode (positive electrode) and a platinum electrode (negative electrode) were inserted with a plate spacing of 1.0 cm. The current was adjusted to a constant current of 8 mA, and the reaction was stirred at 80°C for 6 h. The reaction was monitored by TLC to completion. The reaction was stopped and heated. After the reaction solution cooled to room temperature, the graphite felt electrode was washed three times with dichloromethane. The washings were combined and the graphite felt electrode was immersed in the washings and subjected to microwave sonication for 5 minutes. The reaction solution and electrode washings were combined, and the solvent was evaporated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to obtain 214.49 mg of a light yellow solid. Yield: 90.02% (compared to theoretical yield).

[0053] Structural formula (Ia) is:

[0054] 1H NMR(600MHz,Chloroform-d)δ8.39–8.34(m,1H),8.14(d,J=8.2Hz,1H),7.78(t,J=8.2Hz,1 H),7.73–7.68(m,2H),7.53(q,J=4.8Hz,3H),7.44–7.41(m,1H),7.40–7.36(m,2H),7.22(d, J=7.8Hz,1H),7.14(dd,J=11.8,7.2Hz,2H),6.94(t,J=7.4Hz,1H),6.89–6.79(m,2H),3.78 (dd,J=14.4,7.2Hz,1H),3.68(dd,J=14.4,11.7Hz,1H),3.62(s,3H),1.81(d,J=2.6Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ172.37,157.19,142.97,138.18,132.14,130.77 ,130.33(d,J=2.7Hz),129.61(d,J=9.6Hz),129.18(d,J=9.5Hz),128.26,127. 48–127.19(m),126.30(d,J=11.9Hz),125.31,121.90,121.25,114.58,111.01 ,109.88,47.87(d,J=4.0Hz),39.45(d,J=70.1Hz),31.16(d,J=14.3Hz),29.08. 31 P NMR(202MHz,Chloroform-d)δ27.84.HRMS(ESI)calcd for C 30 H 25 N2O2P[M+H] + :477.1732,found:477.1522.

[0055] Example 2

[0056] This example differs from Example 1 only in that tetrabutylammonium hexafluorophosphonate is replaced by tetrabutylammonium chloride in equal moles. After separation by silica gel column chromatography, 95.32 mg of pale yellow solid Ia is obtained. Yield: 40%.

[0057] Example 3

[0058] This example differs from Example 1 only in that tetrabutylammonium hexafluorophosphonate is replaced with tetrabutylammonium acetate in equal moles. A pale yellow solid Ia (47.65 mg) is obtained by silica gel column chromatography. Yield: 20%.

[0059] Example 4

[0060] The only difference between this example and Example 1 is that the platinum electrode is replaced by a nickel plate electrode. 173.93 mg of light yellow solid Ia is obtained by silica gel column chromatography. Yield: 73%.

[0061] Example 5

[0062] The only difference between this example and Example 1 is that the current was adjusted to 3 mA, and the product Ia (48.04 mg) was obtained by silica gel column chromatography. Yield: 20.16%.

[0063] Example 6

[0064] The only difference between this example and Example 1 is that the current was adjusted to 5 mA, and the product Ia was separated by silica gel column chromatography to obtain 142.95 mg of a pale yellow solid. Yield: 59.99%.

[0065] Examples 7 to 10

[0066] The only difference between Examples 7 to 10 and Example 1 is that 3 mL of acetonitrile and 3 mL of 1,4-dioxane are replaced with 6 mL of acetonitrile, 6 mL of tetrahydrofuran, 3 mL of acetonitrile and 3 mL of tetrahydrofuran, 3 mL of acetonitrile and 3 mL of methanol, respectively. Examples 7 to 10 are separated by silica gel column chromatography to respectively obtain light yellow solid Ia, Example 7: 131.041 mg, yield: 55%; Example 8: 102.45 mg, yield: 43%; Example 9: 147.72 mg:, yield: 62%; Example 10: 193.30 mg, yield: 81.13%.

[0067] Examples 11 to 13

[0068] The only difference between Examples 11 to 13 and Example 1 is that the base (triethylamine) is replaced by equimolar amounts of sodium carbonate, sodium bicarbonate, and 1,4-dimethylaminopyridine, respectively. Examples 11 to 13 are separated by silica gel column chromatography to respectively obtain light yellow solid Ia, Example 11: 194.92 mg, yield: 81.81%; Example 12: 119.37 mg, yield: 50.10%; Example 13: 200.16 mg, yield: 84.01%.

[0069] Example 14

[0070] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(2,4'-dimethyl-[1,1'-biphenyl]-3-yl)-N-methyl methacrylamide in equal moles. Silica gel column chromatography is used to obtain 74.21 mg of a light yellow solid. Yield: 30.26%.

[0071] Structural formula (Ib) is:

[0072] 1 H NMR(600MHz,Chloroform-d)δ8.26(d,J=8.4Hz,1H),8.11(d,J=8.4Hz,1H),7.77–7.75(m,1H),7.72–7.68(m,2H),7.51–7. 36(m,5H),7.17(q,J=9.8,8.6Hz,3H),6.99(s,1H),6.88(s,2H),3.77–3.66(m,2H),3.61(s,3H),2.49(s,3H),1.79(s,3H). 13 C NMR (150MHz, Chloroform-d) δ 173.45, 158.20, 144.12, 138.83 (d, J = 115.0Hz), 131. 73,131.36,130.69(d,J=9.3Hz),130.32(d,J=9.6Hz),129.91(d,J=2.4Hz),128.89– 128.78(m),128.38(d,J=11.5Hz),128.09,127.39(d,J=12.0Hz),122.08,120.67,1 15.50,111.76,110.46,48.97,40.45(d,J=70.6Hz),32.95–32.00(m),30.12,21.41. 31 P NMR(202MHz,Chloroform-d)δ27.95.HRMS(ESI)calcd for C 31 H 28 N2O2P[M+H] + :491.1888,found:491.1826.

[0073] Example 15

[0074] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with an equal molar amount of N-(2-cyano-4'-(methyldimethylene-λ6-sulfanyl)-[1,1'-biphenyl]-3-yl)-N-methylmethacrylamide. Silica gel column chromatography yielded 135.870 mg of a white solid. Yield: 48.99%.

[0075] The structural formula (Ic) is:

[0076] 1H NMR(600MHz,Chloroform-d)δ8.54(d,J=9.2Hz,1H),8.18(d,J=8.2Hz,1H),8.03–7.96( m,2H),7.88(t,J=8.2Hz,1H),7.68(dd,J=11.8,7.2Hz,2H),7.45–7.43(m,1H),7.39(td ,J=7.62.6Hz,2H),7.35(d,J=8.0Hz,1H),7.21–7.16(m,2H),7.08–7.04(m,1H),6.97(t d,J=7.6,2.8z,2H),3.79–3.72(m,2H),3.63(s,3H),3.11(s,3H),1.79(d,J=2.4Hz,3H). 13 C NMR(150MHz,Chloroform-d)δ173.19,161.09(d,J=2.3Hz),143.21,139.73(d,J=2.1Hz),134.12 (dd,J=184.2,99.4Hz),132.87,132.17,131.57(d,J=2.7Hz),130.70–130.46(m),130.23(d,J=9 .4Hz),129.32,128.52(d,J=11.7Hz),127.63(d,J=11.9Hz),126.69,124.11,123.18,116.11,11 2.77(d,J=13.0Hz), 49.31(d,J=4.3Hz), 44.54, 40.08(d,J=70.2Hz), 32.11(d,J=14.1Hz), 30.24. 31 P NMR(202MHz,Chloroform-d)δ28.09.HRMS(ESI)calcd for C 31 H 27 N2O4PS[M+H] + :555.1507,found:555.1347.

[0077] Example 16

[0078] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(2-cyano-4'-methoxy-[1,1'-biphenyl]-3-yl)-N-methyl methacrylamide in equal moles. Silica gel column chromatography yields 185.10 mg of a pale yellow solid. Yield: 73.09%.

[0079] The structural formula (Id) is:

[0080] 1 H NMR(600MHz,Chloroform-d)δ8.27–8.23(m,1H),8.03(dd,J=8.6,2.0Hz,1H),7.78–7.67(m,3H),7.43–7.36(m,3H),7.21–7.12(m,4H),7.03(t,J=7. 4Hz, 1H), 6.93 (td, J = 7.6, 2.8Hz, 2H), 6.85 (d, J = 2.7Hz, 1H), 3.89 (d, J = 1. 0Hz, 3H), 3.73 (qd, J = 14.2, 9.4Hz, 2H), 3.61 (s, 3H), 1.79 (d, J = 2.4Hz, 3H). 13 C NMR(150MHz,Chloroform-d)δ173.44,159.85,158.79(d,J=2.1Hz),145.74,139.23,133 .39(d,J=4.2Hz),131.86,131.36(d,J=2.7Hz),130.53(dd,J=52.4,9.5Hz),130.07(d,J =2.7Hz),127.90(dd,J=144.5,11.8Hz),123.52,117.66,117.14,115.22,111.27,109.8 3,108.82,55.46,49.05(d,J=4.2Hz),40.24(d,J=70.3Hz),32.23(d,J=14.2Hz),30.10. 31 P NMR(202MHz,Chloroform-d)δ40.33.HRMS(ESI)calcd for C 31 H 28 N2O3P[M+H] + :507.1838,found:507.1513.

[0081] Example 17

[0082] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(4'-tert-butyl-2-cyano-[1,1'-biphenyl]-3-yl)-N-methyl methacrylamide in equal moles. Silica gel column chromatography yields 159.20 mg of a pale yellow solid. Yield: 59.78%.

[0083] Structural formula (Ie) is:

[0084] 1H NMR(600MHz,Chloroform-d)δ8.30(d,J=8.6Hz,1H),8.12(d,J=8.2Hz,1H),7.78–7.70( m,3H),7.61(dd,J=8.6,2.2Hz,1H),7.45–7.37(m,4H),7.19(d,J=7.0Hz,1H),7.14(dd,J =11.8,7.6Hz,2H),6.94(t,J=7.6Hz,1H),6.87(td,J=7.2,6.7,3.9Hz,2H),3.80(dd,J= 14.4,7.2Hz,1H),3.71(dd,J=14.2,11.6Hz,1H),3.62(s,3H),1.80(s,3H),1.42(s,9H). 13 C NMR(150MHz,Chloroform-d)δ173.58,158.08,151.58,143.99,139.21,131.73,131.37(d ,J=2.8Hz),130.68(d,J=9.5Hz),130.28(d,J=9.6Hz),130.08(d,J=2.8Hz),128.41(d,J=1 1.7Hz),127.33(d,J=11.9Hz),124.89(d,J=51.8Hz),121.99,120.57,115.53,111.90,11 0.51, 49.01 (d, J = 4.2Hz), 40.26 (d, J = 70.1Hz), 34.87, 32.28 (d, J = 14.2Hz), 31.34, 30.12. 31 P NMR(202MHz,Chloroform-d)δ28.02.HRMS(ESI)calcdfor C 34 H 34 N2O2P[M+H] + :533.2358,found:533.2228.

[0085] Example 18

[0086] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(2-cyano-2'-fluoro-[1,1'-biphenyl]-3-yl)-N-methyl methacrylamide in equal moles. Silica gel column chromatography is used to obtain 202.70 mg of a white solid. Yield: 81.98%.

[0087] The structural formula (If) is:

[0088] 1H NMR(600MHz,Chloroform-d)δ8.54(dd,J=8.4,1.8Hz,1H),7.78(t,J=8.2Hz,1H),7.68–7.64(m,2H),7.52–7.37(m,3H),7.34(td,J=7.62.2Hz,2 H),7.26–7.16(m,2H),7.15–7.10(m,2H),6.97(td,J=7.4,1.6Hz,1H),6 .88(td,J=7.6,2.8Hz,2H),3.71–3.62(m,2H),3.59(s,3H),1.77(s,3H). 13 CNMR(150MHz,Chloroform-d)δ173.11,161.23,159.52(d,J=4.9Hz),145.84,139.07, 132.43,131.41,130.91,130.85,130.64(d,J=9.7Hz),130.30–130.11(m),128.41(d,J =11.9Hz),127.45(d,J=11.9Hz),125.27,120.66(d,J=23.2Hz),112.63(d,J=23.9Hz), 112.42, 111.67, 48.87 (d, J = 4.2Hz), 40.51 (d, J = 70.2Hz), 32.04 (d, J = 14.2Hz), 30.21. 31 P NMR(202MHz,Chloroform-d)δ27.78. 19 F NMR(471MHz,Chloroform-d)δ-111.13(d,J=16.9Hz).HRMS(ESI)calcd for C 30 H 25 FN2O2P[M+H] + :495.1638,found:495.1614.

[0089] Example 19

[0090] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(2-cyano-3-(naphthalen-2-yl)phenyl)-N-methylmethacrylamide in equal moles. Silica gel column chromatography is used to obtain 179.073 mg of a white solid. Yield: 68.01%.

[0091] The structural formula (Ig) is:

[0092] 1H NMR(600MHz,Chloroform-d)δ8.46(d,J=8.4Hz,1H),8.20–8.16(m,2H),7.99(dd,J=13.4,8.2H z,2H),7.93(t,J=9.4Hz,2H),7.89(dd,J=8.5,1.8Hz,1H),7.81(s,1H),7.73(ddd,J=11.5,8.3 ,1.5Hz,2H),7.58–7.53(m,2H),7.44(td,J=7.2,1.4Hz,1H),7.40(td,J=7.6,2.8Hz,2H),7.20 (dd,J=11.2,6.6Hz,2H),6.92(s,1H),3.78(dt,J=25.6,10.2Hz,2H),3.65(s,3H),1.85(s,3H). 13 C NMR(150MHz,Chloroform-d)δ173.5,158.9,144.4,140.7,139.4,137.5,135.4,134.8, 133.8,132.9,132.0,131.4(d,J=2.5Hz),130.7,130.7,130.4,130.3,130.1(d,J=2.7H z),128.7,128.5-128.3(m),127.8,127.5(d,J=12.0Hz),126.5,126.3,126.0,125.4,1 23.0,122.2,115.7,112.1,111.0,49.1,40.5(d,J=70.3Hz),32.2(d,J=14.2Hz),30.2. 31 P NMR(202MHz,Chloroform-d)δ27.95.HRMS(ESI)calcd for C 34 H 27 FN2O2P[M+H] + :527.1888,found:527.2445.

[0093] Example 20

[0094] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(3'-chloro-2-cyano-[1,1'-biphenyl]-3-yl)-N-methyl methacrylamide in equal moles. Silica gel column chromatography yields 130.21 mg of a pale yellow solid. Yield: 50.97%.

[0095] Structural formula (Ih) is:

[0096] 1 H NMR(600MHz,Chloroform-d)δ8.30–8.24(m,1H),8.12–8.07(m,1H),7.82(qd,J=7.6,7.0,3.0Hz,1H),7.72–7.66(m,3H),7.45–7.38(m,4H),7. 29–7.26(m,1H),7.04(ddd,J=11.8,8.1,1.5Hz,2H),6.83–6.72(m,3H),3.84(dd,J=14.3,6.5Hz,1H),3.68–3.60(m,4H),1.91(d,J=2.5Hz,3H). 13 CNMR(150MHz,Chloroform-d)δ173.3,158.9(d,J=2.2Hz),140.3,139.5,135.1,134.4,133 .9,132.9,132.8,132.4,132.2,131.4(d,J=2.7Hz),130.5(d,J=9.4Hz),130.1(d,J=9.6Hz ),129.7(d,J=2.8Hz),128.9,128.4(d,J=11.7Hz),127.2(d,J=11.9Hz),126.1,124.5,121 .2,115.6,112.4,111.4,48.6(d,J=3.9Hz),41.7(d,J=69.7Hz),32.5(d,J=14.2Hz),30.1. 31 P NMR(202MHz,Chloroform-d)δ27.70.HRMS(ESI)calcd for C 30 H 25 ClN2O2P[M+H] + :511.1342,found:511.1214.

[0097] Example 21

[0098] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with an equal molar amount of N-(2-cyano-4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)-N-methyl methacrylamide. 127.96 mg of a light yellow solid is obtained by silica gel column chromatography. Yield: 46.99%.

[0099] Structural formula (Ii) is:

[0100] 1H NMR(600MHz,Chloroform-d)δ8.47(d,J=8.6Hz,1H),8.18(d,J=8.2Hz,1H),7.87(t,J=8.0Hz,1H),7.73–7.68(m,3H),7.63(s,1H),7.45–7.38(m,3 H),7.32(d,J=7.9Hz,1H),7.15(dd,J=11.7,7.5Hz,2H),7.01(t,J=7.4Hz ,1H),6.95–6.90(m,2H),3.77(d,J=9.4Hz,2H),3.65(s,3H),1.80(s,3H). 13 C NMR(150MHz,Chloroform-d)δ173.34,160.24(d,J=2.3Hz),139.68,134.26(dd,J=200.6,9 9.3Hz),132.63,132.46,131.51(d,J=2.7Hz),130.64(d,J=9.6Hz),130.34(d,J=2.9Hz),1 30.19,128.50(d,J=11.6Hz),127.52(d,J=12.0Hz),126.81,125.22,123.37,122.07,115. 86,112.58,112.13,49.23(d,J=4.2Hz),40.25(d,J=70.3Hz),32.07(d,J=14.0Hz),30.23. 31 P NMR(202MHz,Chloroform-d)δ27.97. 19 F NMR(471MHz,Chloroform-d)δ-62.38.HRMS(ESI)calcd forC 31 H 25 F3N2O2P[M+H] + :545.1606,found:545.1456.

[0101] Example 22

[0102] The only difference between this example and Example 1 is that the N-aryl acrylamide compound is replaced with N-(2-cyano-[1,1'-biphenyl]-3-yl)-N-ethyl methacrylamide in equal moles. 131.88 mg of a light yellow solid is obtained by silica gel column chromatography. Yield: 53.77%.

[0103] The structural formula (Ij) is:

[0104] 1H NMR(600MHz,Chloroform-d)δ8.34(d,J=9.0Hz,1H),8.08(d,J=8.3Hz,1H),7.70–7.67(m,2H),7.44(qd,J=7.4,1.8Hz,4H),7.39– 7.37(m,2H),7.30(dd,J=8.8,2.6Hz,1H),7.23(t,J=7.6Hz,1H),7.14–7.11(m,3H),6.89–6.86(m,2H),3.62(s,7H),1.76(s,3H). 13 C NMR(150MHz,Chloroform-d)δ172.97,158.61,143.99,138.10,135.73–133.93( m),133.55,131.79,131.31(d,J=2.5Hz),130.60(dd,J=47.5,9.6Hz),130.20(d ,J=2.9Hz),129.24,128.00(dd),126.29,123.05,122.29,115.46,112.27,110. 81, 49.10 (d, J = 4.3Hz), 39.93 (d, J = 70.3Hz), 37.73, 32.33 (d, J = 14.3Hz), 11.88. 31 P NMR(202MHz,Chloroform-d)δ28.07.HRMS(ESI)calcd for C 31 H 28 N2O2P[M+H] + :491.1888,found:491.1436.

[0105] Example 23

[0106] This example differs from Example 1 only in that the N-aryl acrylamide compound is replaced with N-(2-cyano-[1,1′-biphenyl]-3-yl)-N-methyl methacrylamide in equal moles. 131.92 mg of a light yellow solid is obtained by silica gel column chromatography. Yield: 54%.

[0107] The structural formula (Ik) is:

[0108] 1H NMR(600MHz,Chloroform-d)δ8.53(d,J=8.2Hz,1H),8.22(d,J=8.2Hz,1H),8.04(d,J=8.2Hz,1H),7 .79–7.71(m,2H),7.62(t,J=7.2Hz,1H),7.21(d,J=7.8Hz,1H),3.59(s,3H),3.25(d,J=14.2Hz,1H) ,2.98–2.93(m,1H),2.02(d,J=23.2Hz,2H),1.83(s,3H),1.70(d,J=9.8Hz,5H),1.51(d,J=10.2Hz, 3H), 1.41 (d, J = 16.5Hz, 3H), 1.25 (dt, J = 7.2, 4.2Hz, 5H), 0.96 (dd, J = 9.6, 4.4Hz, 3H), 0.07 (s, 3H). 13 C NMR(150MHz,Chloroform-d)δ172.8,159.2,143.2,138.5,132.3,130.8,128.1,127.8,125.4,122.3,121.8,114.6,111.1, 110.0, 47.9 (d, J = 4.2Hz), 37.8 (t, J = 62.3Hz), 31.9 (d, J = 12.8Hz), 31.1 (d, J = 58.9Hz), 29.0, 26.0-25.6 (m), 25.2-24.6 (m). 31 P NMR(202MHz,Chloroform-d)δ48.55.HRMS(ESI)calcd for C 30 H 28 N2O2P[M+H] + :489.2671,found:489.2428.

[0109] Example 24

[0110] The only difference between this example and Example 1 is that the symmetrical phosphono compound is replaced by bis(4-fluorophenyl)phosphine oxide in equal moles. 143.49 mg of a light yellow solid is obtained by silica gel column chromatography. Yield: 56%.

[0111] Structural formula (I1) is:

[0112] 1H NMR(600MHz,Chloroform-d)δ8.41(dd,J=7.6,1.8Hz,1H),8.17(d,J=8.2Hz,1H),7.80(t,J=8.0Hz,1H),7.69(dtd,J=11.2,5.6,2.0Hz,2H),7.61–7.52( m,3H),7.23(d,J=7.8Hz,1H),7.14–7.05(m,4H),6.56(td,J=8.6,2.0Hz,2H) ,3.73(dd,J=14.4,7.2Hz,1H),3.68–3.64(m,1H),3.63(s,3H),1.80(s,3H). 13 C NMR(150MHz,Chloroform-d)δ173.36,164.39(ddd,J=252.2,116.7,3.2Hz),158.08 ,143.96,139.19,132.88(ddd,J=74.2,11.1,8.7Hz),131.99,131.15,130.46,129. 42,129.08,128.69(d,J=17.4Hz),126.64,122.93,122.37,115.97–114.66(m),112 .02,111.02,48.99(d,J=4.0Hz),40.56(d,J=71.2Hz),32.20(d,J=14.3Hz),30.15. 31 P NMR(202MHz,Chloroform-d)δ27.19. 19 FNMR(471MHz,Chloroform-d)δ-107.36,-108.68.HRMS(ESI)calcd for C 30 H 24 F2N2O2P[M+H] + :513.1543,found:513.1573.

[0113] The anti-tumor activity of the phosphine-containing phenanthridine derivatives obtained in Examples 14 to 24 was tested. The test method and results are as follows:

[0114] (1) Main experimental instruments and reagents used in the test (as shown in Table 1)

[0115] Table 1 Main experimental instruments and reagents used in the test

[0116] Instrument and reagent name Manufacturer DMEM medium ThermoFisher, USA Fetal bovine serum GIBCO Corporation of the United States 0.25% trypsin American Hydrone Company Phosphate buffer Beijing Bailingwei Technology Co., Ltd. Cisplatin Beijing Bailingwei Technology Co., Ltd. Cell Counting Kit-8 (CCK8) Sigma Corporation of America Penicillin-Streptomycin dual antibody solution American Hydrone Company Dimethyl sulfoxide (DMSO) Tianjin Kermiou Chemical Reagent Co., Ltd. SW-CJ-2FD clean bench Jiangsu Antai Air Technology Co., Ltd. MCO-18AC Carbon Dioxide Incubator Panasonic Healthcare Co., Ltd. DT5-3 Medical Centrifuge (DT5-3) Beijing New Era Beili Medical Equipment Co., Ltd. DK-8D three-hole electric constant temperature water tank Shanghai Yiheng Scientific Instrument Co., Ltd. EM208S inverted electron microscope Philips of the Netherlands SAFIRE2 Multifunctional Microplate Reader Swiss Tecan Ultra-low temperature refrigerator Sanyo Corporation of Japan Micropipette Beijing Dalong Xingchuang Experimental Instrument Co., Ltd. Cell counting chamber German Brand Company PURELABPLUS Ultrapure Water System Ball Corporation

[0117] (2) Selection of test cells and test compounds

[0118] In this test, cisplatin was selected as the compound of the positive control group, and the phosphine-containing pyridophenanthridinone derivatives obtained in Examples 14 to 24 were selected as the compounds of the test group.

[0119] In this test, human breast cancer cells (MCF-7) were selected as test cells.

[0120] (3) Test method:

[0121] Cell Counting Kit-8 reduction (CCK8) method: Test cells in the logarithmic growth phase were collected and seeded into 96-well culture plates at a cell number of 5.0×103 / 150μL per well. The cells were cultured in a 37°C, 5% CO2 incubator. The next day, the culture medium was removed and 150μL of different concentrations of compound were added (compound concentrations were diluted in pairs, and each compound was set at 80μmol / L, 40μmol / L, 20μmol / L, 10μmol / L, 5μmol / L, and 2.5μmol / L, a total of 6 concentrations. Each test had 3 parallel wells and was repeated 3 times). No compound was added to the negative control group. After 48 hours, 10μL of 5% CCK8 working solution was added to each well. After another 4 hours of incubation, the absorbance (OD) value of each well at 520nm was measured using a microplate reader to calculate the cell growth inhibition rate.

[0122] The IC value of the drug was calculated based on the cell growth inhibition rate (%) of the drug at different drug concentrations. 50 IC 50 : The concentration of the test compound that inhibits 50% of cell growth.

[0123] (4) The anti-tumor activity test results of the phosphorus-containing pyridophenanthridine ring derivatives obtained in Examples 14 to 24 are shown in Table 2.

[0124] In vitro antitumor activity (IC 50 , μmol / L) as shown in Table 2

[0125] Table 2 Activity (IC 50 , μmol / L)

[0126] Compound MCF-7 Compound MCF-7 Example 14 13.305 Example 20 15.683 Example 15 11.950 Example 21 13.058 Example 16 11.696 Example 22 9.229 Example 17 15.332 Example 23 2.213 Example 18 6.762 Example 24 5.804 Example 19 10.027 Cisplatin 4.259

[0127] As shown in Table 2, the phosphine-containing pyridophenanthridone derivatives obtained in Examples 16, 19 and 22 showed a strong inhibitory effect (IC50 <10 μmol / L) on the MCF-7 cell line and have the potential for further development. Compared with Cisplatin, the overall activity of these compounds is lower, but through structural optimization and mechanism research, it may be possible to develop highly effective and low-toxic anti-tumor drugs. In particular, the IC50 values ​​of Examples 18 and 22 are 6.762 and 5.804, respectively, which are the most active compounds among the selected pyridophenanthridone derivatives, and their inhibitory effects are close to Cisplatin, indicating that they have significant anti-tumor potential. The IC50 value of Example 23 is 2.213, and its anti-proliferative effect on the MCF-7 cell line far exceeds that of the positive control (Cisplatin), indicating that it has excellent anti-tumor effects and can provide new ideas for the subsequent development of anti-tumor drugs.

[0128] Example 25

[0129] N-(2-cyano-[1,1'-biphenyl]-3-yl)-N-methylmethylacrylamide (132.7 mg, 0.5 mmol), diphenylphosphine oxide (252.7.0 mg, 2.5 mmol), ferrocene (46.5 mg, 0.5 mmol), triethylamine (50.6 mg, 0.2 mmol), tetrabutylammonium hexafluorophosphonate (484.3 mg, 0.5 mmol), acetonitrile (3 mL) and 1,4-dioxane (6 mL) were added to a reaction tube, and a graphite felt electrode (positive electrode) and a platinum electrode (negative electrode) were inserted with a plate spacing of 1.0 cm. The current was adjusted to a constant current of 8 mA. The reaction was stirred at 20°C for 10 h and the reaction was monitored by TLC to completion. Stop the reaction and heat. After the reaction solution cools to room temperature, wash the graphite felt electrode three times with dichloromethane. Combine the washings and soak the graphite felt electrode in the washings for 5 minutes under microwave sonication. Combine the reaction solution and electrode washings, and evaporate the solvent under reduced pressure. Separate the concentrate by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to obtain a pale yellow solid.

[0130] Example 26

[0131] N-(2-cyano-[1,1'-biphenyl]-3-yl)-N-methylmethacrylamide (132.7 mg, 0.5 mmol), diphenylphosphine oxide (252.7.0 mg, 0.5 mmol), ferrocene (46.5 mg, 0.2 mmol), triethylamine (50.6 mg, 1 mmol), tetrabutylammonium hexafluorophosphonate (484.3 mg, 2 mmol), acetonitrile (3 mL), and 1,4-dioxane (6 mL) were added to a reaction tube. A graphite felt electrode (positive electrode) and a platinum electrode (negative electrode) were inserted with a spacing of 1.0 cm. The current was adjusted to a constant current of 8 mA. The reaction was stirred at 20°C for 16 h and the completion of the reaction was monitored by TLC. The reaction was stopped and the reaction solution was cooled to room temperature. The graphite felt electrode was washed three times with dichloromethane. The washing solutions were combined and the graphite felt electrode was immersed in the washing solutions and subjected to microwave sonication for 5 min. The reaction solution and the electrode washing solution were combined, and the solvent was evaporated under reduced pressure. The concentrate was separated by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to obtain a light yellow solid.

[0132] The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the various embodiments can be referenced to each other.

[0133] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not limited to the embodiments shown herein but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A phosphine-containing pyridophenanthridinone derivative, characterized in that: The structure of the phosphine-containing pyridophenanthridinone derivative is as follows: Among them, R 1 is hydrogen, alkyl, halogen, alkoxy, sulfonyl, trifluoromethyl, or naphthalene ring; R 2 Ethyl; R 3 It is a benzene ring, cyclohexane or a substituted benzene ring.

2. The electrochemical synthesis method of a phosphine-containing pyridophenanthridinone derivative according to claim 1, characterized in that: The steps include: An N-aryl acrylamide compound, a symmetrical phosphonyl compound, an additive, a base, an electrolyte and an organic solvent are mixed, and electricity is applied to react to obtain a phosphine-containing pyridophenanthridinone derivative; The structural formula of the N-aryl acrylamide compound is: Among them, R 1 is hydrogen, alkyl, halogen, alkoxy, sulfonyl, trifluoromethyl, or naphthalene ring; R 2 Ethyl; The structural formula of the symmetrical phosphono compound is: R 3 It is a benzene ring, cyclohexane or a substituted benzene ring.

3. The electrochemical synthesis method of a phosphine-containing pyridophenanthridinone derivative according to claim 2, characterized in that: The molar ratio of the N-aryl acrylamide compound, the symmetrical phosphonic acid compound, the electrolyte, the additive and the base is 1:1-5:1-5:0.2-1:0.2-2; The molar volume ratio of the N-aryl acrylamide compound to the organic solvent is 1 mmol:10-20 mL.

4. The electrochemical synthesis method of a phosphine-containing pyridophenanthridinone derivative according to claim 3, characterized in that: The reaction temperature is room temperature to 80° C.; the reaction time is 4 to 24 hours; and the reaction current is 3 to 8 mA.

5. The electrochemical synthesis method of a phosphine-containing pyridophenanthridinone derivative according to any one of claims 2 to 4, characterized in that: The electrolyte comprises one or more of tetrabutylammonium hexafluorophosphonate, tetrabutylammonium chloride, tetrabutylammonium acetate and tetrabutylammonium perchlorate; The additive is ferrocene; The base includes one or more of triethylamine, cesium carbonate, sodium carbonate, sodium bicarbonate and 1,4-dimethylaminopyridine; The organic solvent includes one or more of acetonitrile, tetrahydrofuran, methanol and 1,4-dioxane.

6. The electrochemical synthesis method of a phosphine-containing pyridophenanthridinone derivative according to claim 5, characterized in that: The energized positive electrode and negative electrode materials independently include graphite felt electrodes, carbon rod electrodes, platinum electrodes or nickel electrodes.

7. Use of a phosphine-containing pyridophenanthridinone derivative prepared by the preparation method according to any one of claims 2 to 6 in the preparation of anti-tumor drugs.

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