Phosphaphenine pyrylium compound and synthesis method thereof
The preparation of phosphazobenzopyran compounds by Cu(CH3CN)4BF4/TMEDA catalyzed reaction solves the problems of complex synthesis and high cost in existing technologies, and realizes the synthesis of highly efficient cytotoxic compounds against human liver cancer cells, which is suitable for industrial production in the pharmaceutical field.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- XUZHOU NORMAL UNIVERSITY
- Filing Date
- 2023-09-25
- Publication Date
- 2026-07-21
AI Technical Summary
Existing technologies have failed to synthesize and study phosphazobenzopyran compounds and their cytotoxicity to Hep G2 human liver cancer cells. Furthermore, the synthesis methods are complex, costly, and unsuitable for industrial production.
Phosphobenzopyran compounds were prepared by reacting propargyl carbonate with o-hydroxyphenyl-substituted phenyl secondary phosphine oxides in isopropanol under Cu(CH3CN)4BF4/TMEDA catalysis and DIPEA as a base. The reaction conditions were mild and simple, making it suitable for industrial production.
The synthesized phosphazobenzopyran compounds exhibit high sensitivity and cytotoxic activity against Hep G2 human liver cancer cells. The synthesis method is low-cost and high-yield, making it suitable for the pharmaceutical field and industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic chemical synthesis, specifically relating to a phosphorobenzopyran compound and its synthesis method. Background Technology
[0002] Phosphine heterocyclic compounds have significant applications in biomedicine, functional materials, and other fields. Six-membered phosphorus-containing heterocyclic skeletons are widely found in bioactive molecules (J.Med.Chem. 2012, 55, 2196; Eur.J.Med.Chem. 2003, 38, 597; Bioorg.Med.Chem. 2009, 17, 3892). Therefore, designing and developing novel six-membered phosphorus-containing heterocyclic skeletons holds great promise for applications. Phosphabezopyrans are a class of six-membered phosphorus-containing heterocyclic compounds that have never been synthesized and studied before, and their synthetic methods and cytotoxicity against Hep G2 liver cancer cells have not been investigated. Summary of the Invention
[0003] One of the objectives of this invention is to provide a phosphazobenzopyran compound that expands the range of chiral indole cyclocyclic compounds. This derivative exhibits good sensitivity and cytotoxic activity against Hep G2 human liver cancer cells.
[0004] The second objective of this invention is to provide a method for synthesizing the above-mentioned phosphabenzopyran compounds. This method is mild, simple, safe and easy to operate, and has the advantages of low cost and high yield.
[0005] To achieve the above objectives, the technical solution adopted by the present invention is: a phosphorobenzopyran compound, the chemical structural formula of which is shown in Formula 3:
[0006]
[0007] In Formula 3, R is selected from one of the following: phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, benzothiophene, and furanyl; R 1 Ar is selected from hydrogen or methyl; Ar is selected from phenyl, halogen-substituted phenyl, methyl-substituted phenyl, or hydroxy-substituted phenyl.
[0008] The present invention also provides a method for synthesizing the above-mentioned phosphazobenzopyran compounds, the specific steps of which are as follows: under the protection of an inert gas, compound propargyl carbonate of formula 1 and phenyl secondary phosphine oxide substituted with o-hydroxyphenyl of formula 2 are added to isopropanol as reactants. Under the catalysis of Cu(CH3CN)4BF4 / TMEDA and with DIPEA as the base, the reaction is stirred at 80°C for 12 hours. The reaction is monitored by TLC until complete. After filtration, concentration and purification, the phosphazobenzopyran compound of formula 3 is obtained.
[0009] The molar ratio between compound propyltriethoxylate of formula 1 and compound phenyl phosphine oxide of formula 2 is 1.2:1; the molar ratio between compound phenyl phosphine oxide of formula 2: Cu(CH3CN)4BF4:TMEDA:DIPEA is 1:0.05:0.06:1.1; and the molar amount of compound phenyl phosphine oxide of formula 2 and the volume ratio of isopropanol is 1 mmol:10 mL.
[0010] The structural formula of compound propyltriethoxycarbonate of formula 1 is as follows: In Formula 1, R is selected from one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, benzothiophene, and furanyl;
[0011] The structural formula of the o-hydroxyphenyl-substituted phenyl secondary phosphine oxide compound of formula 2 is as follows: In Equation 2, R 1 Ar is selected from hydrogen or methyl; Ar is selected from phenyl, halogen-substituted phenyl, methyl-substituted phenyl, or hydroxy-substituted phenyl.
[0012] Preferably, the purification is performed by silica gel column chromatography, and the eluent is a mixture of dichloromethane and ethyl acetate with a volume ratio of 3:1.
[0013] Compared with the prior art, the present invention has the following beneficial effects:
[0014] (1) The phosphorobenzopyran compounds synthesized in this invention are a class of phosphine oxide compounds that have never been synthesized or studied before. Bioactivity tests show that these derivatives have high sensitivity and strong cytotoxic activity against human liver cancer cells Hep G2, indicating that the phosphorobenzopyran compounds synthesized in this invention are expected to be applied in the pharmaceutical field.
[0015] (2) The reaction conditions for synthesizing phosphabenzene pyran compounds are relatively conventional. The reaction process is mild, simple, easy to operate, and low in cost, making it suitable for large-scale industrial production and broadening the scope of application of this method. The present invention uses a variety of substrates as reactants to obtain products with diverse and complex structures and high yields. Detailed Implementation
[0016] The present invention will be further described in detail below with reference to the embodiments.
[0017] In the examples below, unless otherwise stated, propargyl carbonate, o-hydroxyphenyl-substituted phenyl phosphine oxides and other reagents are commercially available or obtained as reported in known literature; the experimental methods are generally performed under standard conditions or conditions recommended by the manufacturer.
[0018] Example 1
[0019] The synthetic route for the phosphotenopyran compound of formula 3aa is as follows:
[0020]
[0021] Under argon protection, 0.01 mmol Cu(CH3CN)4BF4 (5 mol% relative to formula 2a), 0.012 mmol TMEDA (6 mol% relative to formula 2a), 0.22 mmol DIPEA (110 mol% relative to formula 2a), and 1 mL isopropanol were added to a Shrek tube and stirred for 5 minutes. Subsequently, 0.24 mmol propargyl carbonate formula 1a, 0.2 mmol o-hydroxyphenyl-substituted phenyl secondary phosphine oxide formula 2a, and 1 mL isopropanol were added, and the reaction was carried out at 80 °C for 12 hours. The reaction was monitored by TLC until complete. The product was filtered, concentrated, and purified by silica gel column chromatography (eluting buffer was a 3:1 mixture of dichloromethane and ethyl acetate) to obtain the phosphazobenzopyran compound formula 3aa.
[0022] The structural characterization data of product formula 3aa in Example 1 are as follows:
[0023] 95% yield(63.1mg); brown solid; mp100.9–101.5℃; 1 H NMR (400MHz, CDCl3) δ7.70–7.61(m,2H),7.61–7.55(m,1H),7.53–7.39(m,4H),7.36–7.27(m,5H),7.25–7.14(m,2H),5.37(s,1H),3.83(s,2H); 13 C NMR (100MHz, CDCl3) δ165.9,155.7(d,J=3.0Hz),135.2,133.1,131.9(d,J=10.0Hz),131.7(d,J=3.0Hz),131.0(d,J =5Hz),129.4,128.8,128.5,128.4,127.4,125.0(d,J=10.0Hz),118.3(d,J=5.0Hz),94.5,93.5,42.9(d,J=9.0Hz); 31 P NMR (162MHz, CDCl3) δ-1.37; IR (KBr): 3055,1621,1601,1471,1439,1193,1131,760,695cm -1 ;ESI FTMS exact mass calcd for(C21 H 17 O2P+H) + requires m / z 333.1039,foundm / z333.1029.
[0024] Example 2-15
[0025] The synthesis methods of Examples 2-15 are the same as those of Example 1, except that propargyl carbonates with different structures are used as raw materials.
[0026] The reaction synthesis route is shown below:
[0027]
[0028] The products and yields are shown in Table 1 below:
[0029] Table 1. Reactants, products, and yields of Examples 1-15 [a]
[0030]
[0031] [a] Reaction conditions: Formula 1 (0.24 mmol), Formula 2 (0.2 mmol), Cu(CH3CN)4BF4 (0.01 mmol), TMEDA (0.012 mmol), DIPEA (0.22 mmol), i-PrOH (2 mL), reaction at 80 °C for 12 hours.
[0032] Examples 16-23
[0033] The synthesis methods of Examples 16-23 are the same as those of Example 1, except that propargyl carbonates with different structures and o-hydroxyphenyl-substituted phenyl secondary phosphine oxides are used as raw materials.
[0034] The reaction synthesis route is shown below:
[0035]
[0036] The products, enantioselectivity, and yields are shown in Table 2 below:
[0037] Table 2. Reactants, products, and yields of Examples 1 and 16-23 [a]
[0038]
[0039] [a] Reaction conditions: Formula 1 (0.24 mmol), Formula 2 (0.2 mmol), Cu(CH3CN)4BF4 (0.01 mmol), TMEDA (0.012 mmol), DIPEA (0.22 mmol), i-PrOH (2 mL), reaction at 80 °C for 12 hours.
[0040] As shown in Tables 1 and 2, the method of the present invention can not only achieve the synthesis of phosphopropyran compounds in one step, obtain excellent yields, have high atom economy, be environmentally friendly, and have a wide range of applications, but also has readily available raw materials, simple and safe operation, mild reaction conditions, short reaction time, simple post-processing, and diversified product structures. Therefore, it has great implementation value and potential social and economic benefits.
[0041] The phosphazene pyran compounds of the present invention were preliminarily tested using the CCK8 method to determine the cytotoxic activity of some of the synthesized compounds in the embodiments against human liver cancer cells Hep G2 at a concentration of 100 μg / mL. The results are shown in Table 3.
[0042] Experimental Procedure: Hep G2 liver cancer cells were seeded at a density of 5000 cells / 100 μL of medium in 96-well plates and cultured at 37°C with 5% CO2 for 24 hours. Then, the test compound was added to the medium at a concentration of 100 μg / mL, and the cells were cultured for another 24 hours. Cells without the compound served as the control group, and cells with only medium served as the blank group. After the compound stimulation, the culture medium was removed, and 100 μL of DMEM medium containing 10% CCK8 was added to each well. The cells were incubated at 37°C for another hour, followed by shaking the plate for 5 seconds. The optical density (OD) value was read at 450 nm, and the inhibition rate of the test compound was calculated using Originlab software.
[0043] Table 3 shows the cytotoxic activities of some compounds against Hep G2 liver cancer cells in humans.
[0044]
[0045]
[0046] The results showed that all the tested compounds had cytotoxic activity against human liver cancer cells Hep G2, and exhibited excellent inhibitory effects against human liver cancer cells Hep G2 at a concentration of 100 μg / mL. Among them, Examples 6, 16 and 18 showed excellent cytotoxic activity against human liver cancer cells Hep G2.
[0047] This invention further tested the IC50 of the compounds prepared in Examples 6, 16, and 18 against Hep G2 human liver cancer cells through three parallel experiments. 50 IC50 Experimental Procedure: Hep G2 liver cancer cells were seeded at a density of 5000 cells / 100 μL of medium in 96-well plates and cultured at 37°C with 5% CO2 for 24 hours. Then, the test compound was added to the medium at concentrations of 100, 75, 56.25, 42.19, 31.64, 23.73, and 17.8 μg / mL, and the cells were cultured for another 24 hours. Cells without the compound served as the control group, and cells with only medium served as the blank group. After the compound stimulation, the culture medium was removed, and 100 μL of DMEM medium containing 10% CCK8 was added to each well. The cells were incubated at 37°C for another hour, followed by shaking the plate for 5 seconds. The optical density (OD) value was read at 450 nm. The experiment was repeated three times. Finally, the IC50 of the test compound was calculated using Originlab software. 50 The results are shown in Table 4. The data in Table 4 further confirm that the compounds synthesized in this invention exhibit excellent cytotoxic activity against human liver cancer cells (Hep G2).
[0048] Table 4. IC50 of the compounds in this invention against Hep G2 human liver cancer cells. 50
[0049]
[0050] Note: IC in Table 4 50 The half-maximal inhibitory concentration (MCI) is the concentration of the inhibitory component of a drug.
Claims
1. A phosphotyran compound, characterized in that, Its chemical structural formula is shown in Formula 3: ； In Formula 3, R is selected from one of the following: phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, benzothiophene, and furanyl; R 1 Ar is selected from hydrogen or methyl; Ar is selected from phenyl, halogen-substituted phenyl, methyl-substituted phenyl, or hydroxy-substituted phenyl.
2. A method for synthesizing the phosphorobenzopyran compound according to claim 1, characterized in that, The specific steps are as follows: Under the protection of an inert gas, the phenyl secondary phosphine oxides substituted with o-hydroxyphenyl of Formula 1 and Formula 2 are added to isopropanol as reactants. Under the catalysis of Cu(CH3CN)4BF4 / TMEDA and with DIPEA as the base, the reaction is stirred at 80°C for 12 hours. The reaction is monitored by TLC until complete. After filtration, concentration and purification, the phosphazene pyran compounds of Formula 3 are obtained. The molar ratio between compound 1 and compound 2 (o-hydroxyphenyl substituted phenyl secondary phosphine oxide) is 1.2:1; the molar ratio between compound 2 (o-hydroxyphenyl substituted phenyl secondary phosphine oxide): Cu(CH3CN)4BF4: TMEDA: DIPEA is 1:0.05:0.06:1.1; and the molar amount of compound 2 (o-hydroxyphenyl substituted phenyl secondary phosphine oxide) to the volume ratio of isopropanol is 1 mmol: 10 mL. The structural formula of compound 1 is as follows: In Formula 1, R is selected from one of phenyl, halogen-substituted phenyl, methyl-substituted phenyl, methoxy-substituted phenyl, naphthyl, benzothiophene, and furanyl. The structural formula of the o-hydroxyphenyl-substituted phenyl secondary phosphine oxide compound of formula 2 is as follows: In Equation 2, R 1 Ar is selected from hydrogen or methyl; Ar is selected from phenyl, halogen-substituted phenyl, methyl-substituted phenyl, or hydroxy-substituted phenyl.
3. The method for synthesizing a phosphanebenzopyran compound according to claim 2, characterized in that, The purification was performed by silica gel column chromatography, with the eluent being a mixture of dichloromethane and ethyl acetate at a volume ratio of 3:1.