A celecoxib phenanthroline derivative and preparation method thereof

Abstract

The invention discloses a phenanthridine derivative of celecoxib and a preparation method thereof. The present invention carries out phenanthridine modification in the drug celecoxib, and it is prepared as follows: using celecoxib as a starting material, under the joint action of copper sulfate pentahydrate and potassium persulfate, the methyl in the celecoxib structure is first oxidized to an aldehyde group, and then condensation / cyclization reaction occurs with 2-aminobiphenyl compounds under visible light induction, generating corresponding celecoxib phenanthridine derivatives. The present invention carries out phenanthridine modification on the drug celecoxib, provides a new reference for the modification of celecoxib drugs, and gives more possibilities in the drug celecoxib effect; the reaction conditions are mild, green and environmentally friendly, the steps are short, the overall yield is good, the cost is low, and there is important industrial application value.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a celecoxib phenanthroline derivative and a preparation method thereof. Background Art

[0002] Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor and a nonsteroidal anti-inflammatory drug. It is mainly used in the clinical treatment of various inflammatory diseases, such as osteoarthritis and rheumatoid arthritis. In addition, celecoxib has shown effective anti-tumor or chemopreventive effects in vitro and in vivo, and has potential anti-cancer effects in various cancers, such as colorectal cancer, breast cancer and lung cancer. These effects include inhibiting cell growth, promoting apoptotic cell death, immunomodulation, tumor microenvironment regulation and anti-angiogenesis effects.

[0003] The research on optimizing the structure of drugs and synthesizing some drug derivatives in order to find drugs with better efficacy has developed rapidly in recent years and has become an important part of drug research and development. Summary of the invention

[0004] The purpose of the present invention is to provide a celecoxib phenanthridine derivative and a preparation method thereof, thereby realizing the phenanthridine modification of celecoxib.

[0005] In order to achieve the above object, the present invention adopts the following technical solution:

[0006] Provided is a celecoxib phenanthroline derivative, the structural formula of which is as follows:

[0007]

[0008] According to the above scheme, R 1 Selected from -H, -Me, -OMe, -CO 2 Me, -CF 3 One of the.

[0009] According to the above scheme, R 2 Selected from -H, -Me, -OMe, -CO 2 Me, -CF 3 One of the.

[0010] Provided is a method for preparing the above-mentioned celecoxibphenanthridine derivative, comprising the following steps:

[0011] With celecoxib as the starting material, under the joint action of copper sulfate pentahydrate and potassium persulfate, the methyl group in the celecoxib structure is first oxidized to an aldehyde group to obtain 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide, and then condenses / cyclizes with a 2-aminobiphenyl compound under the induction of visible light to generate the corresponding celecoxib phenanthroline derivative; the specific reaction formula is shown below:

[0012]

[0013] According to the above scheme, the added amounts of celecoxib, copper sulfate pentahydrate and potassium persulfate are in a molar ratio of 1:(1-2):(3-5).

[0014] According to the above scheme, the added amount of 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and 2-aminobiphenyl compound is 1:(1.2-1.5) in molar ratio.

[0015] According to the above scheme, the general formula of 2-aminobiphenyl compounds is: in:

[0016] R 1 is -H, -Me, -OMe, -CO 2 Me, -CF 3 One of;

[0017] R 2 is -H, -Me, -OMe, -CO 2 Me, -CF 3 One of them.

[0018] According to the above scheme, the specific steps are as follows:

[0019] 1) adding water to a solid mixture of copper sulfate pentahydrate and potassium persulfate to obtain a blue mixed solution, heating the mixture to 65-80° C., dissolving celecoxib in acetonitrile, and adding the mixture to the mixed solution to obtain a light green solution, then heating the light green solution to reflux for 40-50 minutes, and post-treating to obtain 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide;

[0020] 2) 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and 2-aminobiphenyl compounds are mixed, and then hexafluoroisopropanol (HFIP) is added, and the mixture is reacted at room temperature for 12-18 hours under visible light induction, and the celecoxib phenanthroline derivative is purified.

[0021] Preferably, in step 1), the concentration of celecoxib in acetonitrile is 0.2 mol / L-0.3 mol / L.

[0022] Preferably, in step 1), the post-treatment is: concentration after extraction and purification by column chromatography.

[0023] Preferably, in step 2), the concentration of 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide in hexafluoroisopropanol is 0.1 mol / L-0.2 mol / L.

[0024] Preferably, in step 2), the light source used is a purple LED lamp (3W*2, wavelength 400-430nm).

[0025] The beneficial effects of the present invention are as follows:

[0026] 1. The present invention obtains a celecoxib phenanthridine derivative, realizes the phenanthridine modification of the drug celecoxib, provides a new reference for the modification of celecoxib drugs, and gives the drug celecoxib more possibilities in terms of efficacy.

[0027] 2. The present invention uses celecoxib as a starting material, oxidizes its methyl group to an aldehyde group to provide a reaction site, and then undergoes a condensation / cyclization reaction with a 2-aminobiphenyl compound under the induction of visible light to construct a phenanthridine structure and generate a corresponding celecoxib phenanthridine derivative, thereby successfully achieving the phenanthridine modification of celecoxib; the method has mild reaction conditions, is green and environmentally friendly, has short steps, good overall yield, low cost, and has important industrial application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step 1 of Example 1.

[0029] Figure 2 This is the carbon NMR spectrum of the product obtained in step 1 of Example 1.

[0030] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step 2 of Example 1.

[0031] Figure 4 This is the carbon NMR spectrum of the product obtained in step 2 of Example 1.

[0032] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step 2 of Example 2.

[0033] Figure 6 This is the carbon NMR spectrum of the product obtained in step 2 of Example 2. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0035] Example 1

[0036] Provided is a method for preparing a celecoxib phenanthridine derivative, the specific reaction formula is as follows:

[0037]

[0038] The following steps are involved:

[0039] 1) Add 24 mL of water to a solid mixture of 690 mg (3 mmol) of copper sulfate pentahydrate and 2.433 g (9 mmol) of potassium persulfate to obtain a blue mixed solution, heat to 65° C., dissolve 1.143 g (3 mmol) of celecoxib in acetonitrile (12 mL), and add to the mixed solution to obtain a light green solution, then heat the light green solution to reflux for 45 minutes, monitor the reaction progress by TLC, determine whether the reaction is complete, or whether a certain reactant has been completely reacted, and stop the reaction. Add water and dichloromethane to the reaction mixture, and extract with dichloromethane 3 times, dry the combined organic layer with anhydrous sodium sulfate, add silica gel powder to spin dry the organic phase, purify the product by column chromatography, spin dry the solvent again and evacuate to obtain 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide, with a yield of 61%. Take 10 mg of the purified product obtained in step 1 and dissolve it in 0.10 mL of DMSO-d 6 In the experiment, hydrogen and carbon nuclear magnetic resonance spectra were performed. Figure 1 is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step 1; 1 H NMR (500 MHz, DMSO-d 6 )δ10.03(s,1H),7.92(dd,J=15.9,8.0Hz,4H),7.62–7.52(m,6H),7.39(s,1H). Figure 2 is the carbon NMR spectrum of the product obtained in step 1; 13 C NMR (126 MHz, DMSO-d 6 )δ193.09,144.77,144.56,142.89(q,J=37.8Hz),141.30,136.71,134.1 3,130.18(d,J=5.6Hz),127.44,126.59,121.67(q,J=268.9Hz),107.78.

[0040] 2) 4 mL of hexafluoroisopropanol was added to a solid mixture of 79.01 mg (0.2 mmol) of 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and 43.96 mg (0.26 mmol) of 2-aminobiphenyl. The reaction mixture was reacted at room temperature for 12 hours under irradiation of a purple LED lamp (3W*2, wavelength of 400-430 nm). The reaction progress was monitored by TLC to determine whether the reaction was complete or a certain reactant had reacted completely, and the reaction was stopped. Then, silica gel powder was added to dry the solvent, and the product was purified by column chromatography. The solvent was dried again and vacuumed to obtain 4-(5-(4-(phenanthridin-6-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide with a yield of 75%. 10 mg of the purified product obtained in step 2 was dissolved in 0.10 mL of DMSO-d 6 In the experiment, hydrogen and carbon nuclear magnetic resonance spectra were performed. Figure 3 is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step 2; 1 H NMR (500 MHz, DMSO-d 6 )δ8.93(d,J=8.0Hz,1H),8.83(d,J=8.3Hz,1H),8.10(dd,J=8.1,1.4Hz,1H),7.95(dd,J=15.6,8.2Hz,4H),7 .80(ddd,J=8.3,7.0,1.4Hz,1H),7.77–7.72(m,4H),7.69–7.64(m,2H),7.53(d,J=8.2Hz,4H),7.36(s,1H). Figure 4 This is the carbon NMR spectrum of the product obtained in step 2; 13 CNMR (126MHz, DMSO-d 6 )δ159.99,145.28,144.64,143.60,142.83(q,J=37.8Hz),141.56,140.52,133.30,131.67,130.56,130.20,129.66,129.3 5,129.04,128.36(d,J=7.9Hz),127.95,127.45,126.59,124.66,123.78,123.41,123.19,121.78(q,J=268.7Hz),107.31.

[0041] Example 2

[0042] Provided is a method for preparing a celecoxib phenanthridine derivative, the specific reaction formula is as follows:

[0043]

[0044] The following steps are involved:

[0045] 1) Add 40 mL of water to a solid mixture of 1.150 g (5 mmol) of copper sulfate pentahydrate and 4.055 g (15 mmol) of potassium persulfate to obtain a blue mixed solution, heat to 65° C., dissolve 1.905 g (5 mmol) of celecoxib in acetonitrile (20 mL), and add to the mixed solution to obtain a light green solution, then heat the light green solution to reflux for 45 minutes, monitor the reaction progress by TLC, determine whether the reaction is complete, or whether a certain reactant has been completely reacted, and stop the reaction. Add water and dichloromethane to the reaction mixture, and extract with dichloromethane 3 times, dry the combined organic layer with anhydrous sodium sulfate, add silica gel powder to spin-dry the organic phase, purify the product by column chromatography, spin-dry the solvent again and evacuate to obtain 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide, with a yield of 59%.

[0046] 2) 4 mL of hexafluoroisopropanol was added to a solid mixture of 79.01 mg (0.2 mmol) of 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and 59.04 mg (0.26 mmol) of 2'-amino-[1,1'-biphenyl]-4-carboxylic acid methyl ester. The reaction mixture was reacted at room temperature for 12 hours under irradiation of a purple LED lamp (3W*2, wavelength of 400-430 nm). The reaction progress was monitored by TLC to determine whether the reaction was complete or a certain reactant had reacted completely, and the reaction was stopped. Then, silica gel powder was added to spin dry the solvent, and the product was purified by column chromatography. The solvent was spin dried again and vacuumed to obtain 6-(4-(1-(4-sulfamoylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenyl)phenanthridine-8-carboxylic acid methyl ester, with a yield of 65%. Take 10 mg of the purified product obtained in step 2 and dissolve it in 0.10 mL of DMSO-d 6 In the experiment, hydrogen and carbon nuclear magnetic resonance spectra were performed. Figure 5 is the hydrogen nuclear magnetic resonance spectrum of the product obtained in step 2; 1 H NMR (500 MHz, DMSO-d 6)δ8.97(d,J=8.8Hz,1H),8.81(d,J=7.7Hz,1H),8.51(d,J=1.8Hz,1H),8.3 3(dd,J=8.6,1.7Hz,1H),8.11(dd,J=8.1,1.3Hz,1H),7.97–7.94(m,2H),7 .85(ddd,J=8.2,7.0,1.3Hz,1H),7.78–7.75(m,1H),7.75–7.73(m,2H),7. 69–7.66(m,2H),7.57–7.55(m,2H),7.53(s,2H),7.41(s,1H),3.86(s,3H). Figure 6 This is the carbon NMR spectrum of the product obtained in step 2; 13 C NMR (126 MHz, DMSO-d 6 )δ166.02,160.17,145.13,144.71,144.31,142.85(q,J=37.6Hz),141.58,139.96,136.31,130.87,130.63,130.28,130.02 ,129.42,129.31,128.78,128.35,127.45,126.64,124.98,124.16,123.83,123.05,122.84,120.70,118.57,107.43,53.02.

Claims

1. A method for preparing a celecoxib phenanthridine derivative, characterized in that: The structural formula of the celecoxib phenanthroline derivative is as follows: The preparation method comprises the following steps: Celecoxib is used as a starting material, under the combined action of copper sulfate pentahydrate and potassium persulfate, the methyl group in the celecoxib structure is first oxidized to an aldehyde group to obtain 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide, and then hexafluoroisopropanol is used as a solvent to undergo a condensation / cyclization reaction with a 2-aminobiphenyl compound under the induction of visible light to generate a corresponding celecoxib phenanthroline derivative; The general formula of 2-aminobiphenyl compounds is: ,in: R1 is one of -H, -Me, -OMe, -CO2Me, and -CF3; R2 is one of -H, -Me, -OMe, -CO2Me, and -CF3; The specific reaction formula is as follows: 。 2. The preparation method according to claim 1, characterized in that: The added amounts of celecoxib, copper sulfate pentahydrate and potassium persulfate are in a molar ratio of 1:(1-2):(3-5).

3. The preparation method according to claim 1, characterized in that: The added amount of 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and 2-aminobiphenyl compounds is 1:(1.2-1.5) in molar ratio.

4. The preparation method according to claim 1, characterized in that: The specific steps are as follows: 1) Add water to a solid mixture of copper sulfate pentahydrate and potassium persulfate to obtain a blue mixed solution, heat to 65-80° C., dissolve celecoxib in acetonitrile and add the mixture to the mixed solution to obtain a light green solution, then heat the light green solution to reflux for 40-50 minutes, and post-treat to obtain 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; 2) Mix 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide and 2-aminobiphenyl compounds, then add hexafluoroisopropanol, react at room temperature for 12-18 hours under visible light induction, and purify to obtain celecoxib phenanthroline derivatives.

5. The preparation method according to claim 4, characterized in that: In the step 1), the concentration of celecoxib in acetonitrile is 0.2 mol / L-0.3 mol / L; In the step 2), the concentration of 4-(5-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide in hexafluoroisopropanol is 0.1 mol / L-0.2 mol / L.

6. The preparation method according to claim 4, characterized in that: In the step 2), the light source used is a purple LED lamp.

Images