Nuciferine derivative prepared based on condensation reaction as well as preparation method and application of nuciferine derivative

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a nuciferine derivative prepared based on condensation reaction and a preparation method and application thereof. According to the invention, nuciferine is structurally modified by introducing an active group, the biological activity of nuciferine in reduction of uric acid is improved, and cell experiments find that the alkyl amide nuciferine derivative prepared by the invention can inhibit expression of URAT1 in HK-2 cells and can promote excretion of uric acid, so that the level of uric acid is reduced, and the activity of the nuciferine in reduction of uric acid is improved. The important significance is realized on the further development of new uric acid reducing medicines; the phenoxyacyl nuciferine derivative with the uric acid reducing and kidney protecting effects is simple in synthesis method, low in raw material price and novel in structure.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a nuciferine derivative prepared based on a condensation reaction, and a preparation method and application thereof. Background Art

[0002] Hyperuricemia is a disease caused by purine metabolism disorder in the body, and can cause a series of complications such as gout, hypertension, diabetes, etc. At present, clinical drugs for the treatment of hyperuricemia include allopurinol, probenecid, benzbromarone, etc. These drugs can cause chronic damage to the urinary system including the kidneys, and are prone to the formation of urate crystals and stones.

[0003] Lotus leaf is a plant of the Nymphaeaceae family. Nelumbo nucifera Gaertn. ) is a plant that can be used as both medicine and food. Traditional medicine believes that lotus leaves are bitter and cold in nature, and have the effects of clearing away heat and dampness, promoting the production of yang, clearing the heart and removing heat, stopping bleeding and promoting diuresis. Modern research has confirmed that lotus leaves have a variety of biological activities such as lipid-lowering, antibacterial, sedative and anti-oxidant, and alkaloid compounds are its main active ingredients. This type of compound is mainly divided into monobenzylisoquinolines, aporphines, chemaporphines and dehydroaporphines according to their structural types. Nuciferine is a kind of alkaloid obtained from the Nymphaeaceae plant Nelumbo nucifera ( Nelumbo nucifera Gaertn ) is an alkaloid extracted from . At present, pharmacological studies have shown that it has multiple pharmacological activities such as antioxidant, anti-obesity, anti-inflammatory, anti-atherosclerotic, anti-viral, and anti-tumor. Due to its low toxicity and small side effects, nuciferol has become one of the hot spots in drug research and has broad development prospects. However, nuciferol has low uric acid-lowering activity and cannot be directly used in clinical uric acid-lowering drugs. It is of great significance to develop a uric acid-lowering drug with higher efficacy. Summary of the invention

[0004] In view of the problems existing in the prior art, the present invention provides a nuciferine derivative prepared based on a condensation reaction.

[0005] The invention also provides a preparation method of the nuciferine derivative.

[0006] The present invention further provides the use of the above-mentioned nuciferine derivatives in the preparation of drugs for treating uric acid reduction or protecting kidneys.

[0007] The technical solution adopted by the present invention to achieve the above-mentioned purpose is: The present invention provides a nuciferine derivative prepared based on a condensation reaction, and the molecular structure thereof is: ; R is , , , , .

[0008] The present invention also provides a method for preparing the above-mentioned nuciferine derivative, comprising the following steps: (1) Dissolve nuciferine in methanol, then add hydrogen peroxide and stir to react; after the reaction is completed, adjust the pH value of the reaction solution, then add distilled water, extract with chloroform, dry the chloroform layer with anhydrous Na2SO4, filter to remove the solid, concentrate the filtrate under reduced pressure, separate by silica gel column chromatography, and elute to obtain nuciferine- N - oxides; (2) Under ice bath conditions, N - oxide is dissolved in methanol, and then a methanol solution of FeSO4·7H2O is added, and the reaction is stirred after removing the ice bath to obtain a reaction solution; a saturated NaHCO3 solution is added to the reaction solution to continue the reaction; after the reaction is completed, distilled water is added, and chloroform is extracted, the chloroform layer is dried over anhydrous Na2SO4, the solid is removed by filtration, and the mixture is evaporated to dryness under reduced pressure, and separated by silica gel column chromatography and eluted to obtain proto-nuciferine; (3) Dissolve proto-nuciferine and triethylamine in anhydrous DCM, slowly add RX dropwise while maintaining 0°C, and stir to react. After the reaction is completed, quench the reaction, extract the reaction solution with dichloromethane, dry it with anhydrous sodium sulfate, concentrate the filtrate, and obtain the target compound by column chromatography.

[0009] Furthermore, in step (1), the ratio of nuciferine to hydrogen peroxide is 1 mmol:7.5 mL.

[0010] Furthermore, in step (1), the stirring reaction is carried out at room temperature for 24 hours; the pH is adjusted to 10 using a 3M NaOH aqueous solution; and the elution is carried out using an eluent consisting of chloroform: methanol: triethylamine in a volume ratio of 30:1:1‰.

[0011] Furthermore, in step (2), nuciferine- N -oxide and FeSO4·7H2O molar ratio is 1:2; the concentration of FeSO4·7H2O methanol solution is 1 mol / L; N -The ratio of oxide and saturated NaHCO3 solution is 1mmol:10mL;.

[0012] Furthermore, in step (2), the stirring reaction is carried out at room temperature for 12 hours; the reaction is continued for 20 minutes; and the elution is carried out using an eluent consisting of chloroform: methanol: triethylamine in a volume ratio of 10:1:1‰.

[0013] Furthermore, in step (3), the molar ratio of proto-nuciferine, triethylamine and RX is 1:2-5:1-2.

[0014] Furthermore, in step (3), the stirring reaction is carried out at room temperature for 10-12 hours; and saturated sodium bicarbonate is used to quench the reaction.

[0015] The present invention also provides a use of the nuciferine derivative in preparing a drug for lowering uric acid or protecting kidneys.

[0016] The reaction route for preparing the phenoxyacyl nuciferine derivatives of the present invention is: The beneficial effects of the present invention are: (1) The present invention improves the biological activity of nuciferine in lowering uric acid by introducing active groups to modify the structure of nuciferine. Cell experiments have found that the alkylamide nuciferine derivatives prepared by the present invention can inhibit the expression of URAT1 in HK-2 cells and promote uric acid excretion, thereby reducing uric acid levels, which is of great significance for the further development of new uric acid-lowering drugs; (2) The phenoxyacyl nuciferine derivatives provided by the present invention have uric acid-lowering and kidney-protecting effects, and have a simple synthesis method, low raw material price, and novel structure. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Hydrogen spectrum of compound 22 prepared in Example 1; Figure 2 Carbon spectrum of compound 22 prepared in Example 1; Figure 3 HRMS pattern of compound 22 prepared in Example 1; Figure 4 Hydrogen spectrum of compound 23 prepared in Example 2; Figure 5 Carbon spectrum of compound 23 prepared in Example 2; Figure 6 HRMS pattern of compound 23 prepared in Example 2; Figure 7 Hydrogen spectrum of compound 13 prepared in Example 3; Figure 8 Carbon spectrum of compound 13 prepared in Example 3; Fig. 9 HRMS pattern of compound 13 prepared in Example 3; Fig.10 Hydrogen spectrum of compound 25 prepared in Example 4; Fig.11 Carbon spectrum of compound 25 prepared in Example 4; Fig.12 HRMS pattern of compound 25 prepared in Example 4; Fig.13Hydrogen spectrum of compound 24 prepared in Example 5; Fig.14 Carbon spectrum of compound 24 prepared in Example 5; Fig.15 HRMS chart of compound 24 prepared in Example 5. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further explained and illustrated by means of specific embodiments below.

[0019] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0020] Example 1 (1) Dissolve nuciferine (0.295 g, 1 mmol) in 15 mL of methanol, then add 7.5 mL of 30% H2O2 to the solution and stir for 24 h at room temperature. After the reaction, add 3M NaOH aqueous solution to the reaction solution to adjust the pH to 10, then add 150 mL of distilled water, extract with chloroform 3 times (600 mL×3), dry the chloroform layer with anhydrous Na2SO4, filter to remove the solid, and concentrate the filtrate under reduced pressure. Separate by silica gel column chromatography, elute with chloroform: methanol: triethylamine (30:1:1‰ v / v / v), and finally obtain nuciferine- N -Oxide.

[0021] (2) Under ice bath conditions, N -oxide (0.310 g, 1 mmol) was dissolved in 2 mL of methanol, and then a methanol solution (2 mL) of FeSO4·7H2O (0.304 g, 2 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 12 h. Finally, 10 mL of saturated NaHCO3 solution was added to the reaction solution and the reaction was continued for 20 min. After the reaction was completed, 90 mL of distilled water was added to the three-necked flask and extracted with chloroform three times (100 mL×3). The chloroform layer was dried over anhydrous Na2SO4, the solid was removed by filtration, and it was evaporated to dryness under reduced pressure. Separation was performed by silica gel column chromatography and eluted with chloroform: methanol: triethylamine (10:1:1‰) to obtain proto-nuciferine.

[0022] (3) Dissolve proto-nuciferine (0.10 g, 0.31 mmol) and triethylamine (0.12 mL, 0.86 mmol) in anhydrous DCM (20 mL), slowly add 4-methoxyphenyl chloroformate (0.07 g, 0.38 mmol) at 0 °C, and stir the reaction solution overnight at room temperature. After the reaction is completed, quench the reaction with saturated sodium bicarbonate (25 mL), extract the reaction solution with dichloromethane (2×25 mL), and dry it with anhydrous sodium sulfate. Concentrate the filtrate and obtain the target compound 22 by column chromatography as a light yellow powder with mp 173.6–174.6 °C.

[0023] The structural formula of compound 22 is: like Figure 1-Figure 3 As shown: 1 H NMR (600 MHz, CDCl3) δ 8.38 (d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.2 Hz,1H), 7.20 – 7.22 (m, 1H), 7.16 – 7.18 (m, 1H), 6.98 (s, 2H), 6.81 (d, J = 8.2Hz, 2H), 6.64 (s, 1H), 4.84 (d, J = 5.4 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 3.85(s, 3H), 3.72 (s, 3H), 3.61 (s, 3H), 3.16 – 2.87 (m, 4H), 2.66 (d, J = 15.1 Hz,1H). 13 C NMR (151 MHz, CDCl3) δ 156.98, 154.64, 152.24, 145.78, 144.89,136.56, 131.68, 129.61, 128.54, 128.43, 127.80, 127.65, 127.15, 125.83,122.59, 114.37, 111.54, 60.08, 55.99, 55.64, 52.13, 39.22, 36.06, 30.27. HRMS calculation for C 26 H 25NO5: [M+Na] + 454.1630, found 454.1633. Example 2 Steps (1) and (2) are the same as in Example 1; (3) Dissolve proto-nuciferine (0.10 g, 0.31 mmol) and triethylamine (0.12 mL, 0.86 mmol) in anhydrous DCM (20 mL), slowly add p-nitrochloroformate (0.08 g, 0.40 mmol) at 0°C, and stir the reaction solution overnight at room temperature. After the reaction, quench the reaction with saturated sodium bicarbonate (25 mL), extract the reaction solution with dichloromethane (2×25 mL), and dry it with anhydrous sodium sulfate. Concentrate the filtrate and column chromatograph to obtain the target compound 23 as a white powder, mp 145.8-146.8°C.

[0024] The structural formula of compound 23 is: like Figure 4-Figure 6 As shown: 1 H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 8.26 (d, J = 8.3 Hz, 2H), 7.42 –7.31 (m, 3H), 7.29 (d, J = 6.2 Hz, 2H), 6.72 (s, 1H), 4.89 (d, J = 44.3 Hz, 1H),4.55 (d, J = 10.4 Hz, 1H), 3.92 (s, 3H), 3.69 (s, 3H), 3.34 – 2.94 (m, 4H), 2.77 (d, J = 15.4 Hz, 1H). 13 C NMR (151 MHz, CDCl3) δ 156.21, 152.88, 152.41, 145.90, 144.91,136.14, 131.64, 129.38, 128.69, 128.51, 128.27, 127.92, 127.52, 127.40,125.13, 122.36, 111.62, 60.10, 56.00, 52.45, 39.45, 36.26, 30.02. HRMS calculation for C25 H 22 N2O6: [M+Na] + 469.1376, found 469.1380. Example 3 Steps (1) and (2) are the same as in Example 1; (3) Dissolve proto-nuciferine (0.10 g, 0.31 mmol) and triethylamine (0.12 mL, 0.86 mmol) in anhydrous DCM (20 mL), slowly add 3-phenylpropionyl chloride (0.06 g, 0.36 mmol) at 0 °C, and stir the reaction solution overnight at room temperature. After the reaction is completed, quench the reaction with saturated sodium bicarbonate (25 mL), extract the reaction solution with dichloromethane (2×25 mL), and dry it with anhydrous sodium sulfate. Concentrate the filtrate and column chromatography to obtain the target compound 13 as a white powder, mp 149.7–150.7 °C.

[0025] The structural formula of compound 13 is: like Figure 7-Figure 9 As shown: 1 H NMR (600 MHz, CDCl3) δ 8.35 (d, J = 8.0 Hz, 1H), 7.27 – 7.22 (m, 3H), 7.18 – 6.99 (m, 5H), 6.59 (s, 1H), 4.97 (d, J = 11.6 Hz, 1H), 3.92 (d, J = 13.6Hz, 1H), 3.82 (s, 3H), 3.59 (s, 3H), 3.20 – 2.86 (m, 4H), 2.77 – 2.63 (m,3H), 2.58 – 2.50 (m, 2H). 13 C NMR (151 MHz, CDCl3) δ 170.70, 152.05, 145.85, 141.34, 136.84,131.54, 130.23, 128.64, 128.56, 128.52, 128.03, 127.77, 127.42, 126.98,126.23, 125.54, 111.22, 60.03, 55.99, 50.63, 41.08, 36.68, 34.05, 31.51,30.73. HRMS calculation for C 27 H 27 NO3: [M+Na] + 436.1889, found 436.1892. Example 4 Steps (1) and (2) are the same as in Example 1; (3) Dissolve proto-nuciferine (0.10 g, 0.31 mmol) and triethylamine (0.12 mL, 0.86 mmol) in anhydrous DCM (20 mL), slowly add benzyloxyacetyl chloride (0.07 g, 0.38 mmol) at 0 °C, and stir the reaction solution overnight at room temperature. After the reaction is completed, quench the reaction with saturated sodium bicarbonate (25 mL), extract the reaction solution with dichloromethane (2×25 mL), and dry it with anhydrous sodium sulfate. Concentrate the filtrate and column chromatography to obtain the target compound 25 as a white powder, mp 132.3–133.3 °C.

[0026] The structural formula of compound 25 is: like Figure 10-12 As shown: 1 H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 7.9 Hz, 1H), 7.43 – 6.96 (m, 8H), 6.65 (s, 1H), 5.16 – 4.82 (m, 1H), 4.71 – 4.48 (m, 2H), 4.38 – 4.02 (m, 3H), 3.89 (s, 3H), 3.66 (s, 3H), 3.35 – 2.95 (m, 2H), 2.89 – 2.62 (m, 3H). 13 C NMR (151 MHz, CDCl3) δ 167.92, 152.15, 145.87, 137.33, 136.61,131.53, 129.94, 128.65, 128.52, 128.10, 128.01, 127.82, 127.35, 127.04,126.08, 125.50, 111.29, 73.28, 60.04, 55.99, 50.74, 40.81, 36.88, 33.97,30.78. HRMS calculation for C 27 H 27NO4: [M+Na] + 452.1838, found 452.1838. Example 5 Steps (1) and (2) are the same as in Example 1; (3) Dissolve proto-nuciferine (0.10 g, 0.31 mmol) and triethylamine (0.12 mL, 0.86 mmol) in anhydrous DCM (20 mL), slowly add p-nitrobenzyl chloroformate (0.08 g, 0.37 mmol) at 0 °C, and stir the reaction solution overnight at room temperature. After the reaction is completed, quench the reaction with saturated sodium bicarbonate (25 mL), extract the reaction solution with dichloromethane (2×25 mL), and dry it with anhydrous sodium sulfate. Concentrate the filtrate and column chromatograph to obtain the target compound 24 as a white powder with mp 158.3-159.3 °C.

[0027] The structural formula of compound 24 is: like Figure 13-Figure 15 As shown: 1 H NMR (600 MHz, CDCl3) δ 8.45 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 5.2 Hz,2H), 7.52 (d, J = 4.6 Hz, 2H), 7.39 – 7.31 (m, 1H), 7.31 – 7.20 (m, 2H), 6.69(s, 1H), 5.41 – 5.20 (m, 2H), 4.86 – 4.72 (m, 1H), 4.48 (s, 1H), 3.90 (s,3H), 3.67 (s, 3H), 3.14 – 2.82 (m, 4H), 2.70 (d, J = 15.3 Hz, 1H). 13 C NMR (151 MHz, DMSO) δ 154.51, 152.30, 147.49, 145.55, 145.22,136.93, 131.72, 130.08, 128.77, 128.64, 128.41, 128.20, 127.44, 126.90,125.59, 124.04, 112.84, 65.74, 60.04, 56.28, 51.88, 39.12, 35.51, 30.02. HRMS calculation for C 26 H 24 N2O6: [M+Na] + 483.1532, found 483.1529. Effect verification 1. Cell culture and drug administration Cell passaging. When HK-2 cells grow to a density of 85%-90%, the cells are processed for cell passaging. Place the cells in a clean bench, discard the old culture medium with a pipette, add 4.0 mL of PBS to wash, discard the PBS, and repeat 2-3 times. Use a pipette to add 1.0 mL of 0.25% trypsin to digest for 40 seconds, aspirate the trypsin with a pipette, add culture medium and repeatedly blow and beat until it becomes a single cell suspension. Take 1.0 mL of cell suspension and transfer it to a new culture dish, add 7 mL of culture medium, shake well, and transfer the culture dish to a cell culture incubator after microscopic observation.

[0028] Uric acid induction and administration. When the cells were successfully revived and stably cultured for more than three generations, and the cell density of the culture dish reached 85%-90%, the HK-2 cells were taken out of the incubator and placed on an ultra-clean bench. The culture medium was discarded, and the cells were washed three times with PBS to remove dead cells. The culture dishes of the model group and the drug-treated group were added with a culture medium containing 100 mg / L uric acid and a certain amount of the compound solution prepared in the example (the final concentration of the compound was 50 μM), shaken well, marked, and transferred to the incubator for 48 hours for protein extraction and quantitative analysis.

[0029] (II) Cell protein quantification experiment Take the protein standard preparation solution of the BCA kit, add it to the protein standard, prepare a 1 mg / mL protein solution, and dilute the concentration to 0.5, 0.4, 0.2, 0.1, and 0.05 mg / mL for subsequent sample preparation. Take a 50.0 mL centrifuge tube and prepare the BCA colorimetric agent according to the instructions of the kit. Add the diluted protein solution to a 96-well plate, 25 µL per well, and set three replicates for each concentration. Thaw the extracted cell protein in advance and dilute it 40 to 80 times, add it to a 96-well plate, 25 µL per well, and set three replicates for each group. After the protein is loaded, add 125 µL of BCA colorimetric agent, incubate in a constant temperature incubator for half an hour, detect 562 nm with an enzyme marker, make a protein standard curve based on the absorbance value, and substitute the absorbance value of the protein to be tested to obtain the protein concentration.

[0030] (III) Western-Blot 1. Make gel. Take a professional gel glass plate, wash it clean and dry it, clamp it on the mold, inject the lower layer gel prepared according to the instructions for making polyacrylamide gel (PAGE), seal and flatten the gel surface with Wahaha water, let it stand at room temperature for 20-30 min, pour out the Wahaha water after obvious traces of gel and water layer appear, inject the 5% upper layer gel prepared according to the instructions, insert a 10-hole comb, and let it stand at room temperature again for 20-30 min. Insert the prepared gel into the electrophoresis tank, fill it with the prepared 1× electrophoresis solution, and pull out the comb vertically. Add 5 µL of protein marker to one well, and add 60 µg of the above quantified protein to the experimental well. Connect the power supply, constant voltage 120 V, set the time as required, and perform electrophoresis. After the electrophoresis is completed, transfer to the membrane. Cut a 10-hole strip-sized polyvinylidene fluoride (PVDF) membrane, activate it in methanol, and then transfer it to the membrane. After electrophoresis, the constant current was 300 mA and electrotransfer was performed for 60-75 min.

[0031] The transferred PVDF membrane was cut out according to the protein marker ruler to obtain the target band URAT1 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) band, placed in 3.0 mL of pre-cooled 5% milk blocking solution, and blocked on a shaker for 2 h. The blocked target band was placed in an antibody incubation box, and the URAT1 (GLUT9) antibody and GAPDH antibody diluted according to the instructions were added, and incubated in a refrigerator at 4°C overnight. The next day, the URAT1 (GLUT9) and GAPDH solutions were discarded, TBST was added and placed on a shaker for washing 3 times, 5 min each time, and the corresponding secondary antibody was added, and continued to be placed on a shaker for incubation for 2 h. After the binding of the secondary antibody was completed, it was washed, and the enhanced chemiluminescence agent was added and placed in a chemiluminescence imaging system to scan the membrane and take pictures. ImageJ was used to analyze the grayscale value of the protein band, and GraphPad Prism 8.0 software was used to draw and analyze the expression of URAT1 (GLUT9) in each group of cells. The protein expression level percentage was obtained based on the URAT1 protein expression level in the blank group. The specific results are shown in Table 1 Table 1 Experimental results of compounds (50 μM) inhibiting URAT1 expression in HK-2 cells

Claims

1. A nuciferine derivative prepared by condensation reaction, characterized in that: Its molecular structure is: ； R is , , , , .

2. A method for preparing the nuciferine derivative according to claim 1, characterized in that: The following steps are involved: (1) Dissolve nuciferine in methanol, then add hydrogen peroxide and stir to react; after the reaction is completed, adjust the pH value of the reaction solution, then add distilled water, extract with chloroform, dry the chloroform layer with anhydrous Na2SO4, filter to remove the solid, concentrate the filtrate under reduced pressure, separate by silica gel column chromatography, and elute to obtain nuciferine- N - oxides; (2) Under ice bath conditions, N - oxide is dissolved in methanol, and then a methanol solution of FeSO4·7H2O is added, and the reaction is stirred after removing the ice bath to obtain a reaction solution; a saturated NaHCO3 solution is added to the reaction solution to continue the reaction; after the reaction is completed, distilled water is added, and chloroform is extracted, the chloroform layer is dried over anhydrous Na2SO4, the solid is removed by filtration, and the mixture is evaporated to dryness under reduced pressure, and separated by silica gel column chromatography and eluted to obtain proto-nuciferine; (3) Dissolve proto-nuciferine and triethylamine in anhydrous DCM, slowly add RX dropwise while maintaining 0°C, and stir to react. After the reaction is completed, quench the reaction, extract the reaction solution with dichloromethane, dry it with anhydrous sodium sulfate, concentrate the filtrate, and obtain the target compound by column chromatography.

3. The preparation method according to claim 2, characterized in that: In step (1), the ratio of nuciferine to hydrogen peroxide is 1 mmol:7.5 mL.

4. The preparation method according to claim 2 or 3, characterized in that: In step (1), the stirring reaction is carried out at room temperature for 24 hours; the pH is adjusted to 10 using a 3M NaOH aqueous solution; and the elution is carried out using an eluent consisting of chloroform: methanol: triethylamine in a volume ratio of 30:1:1‰.

5. The preparation method according to claim 2, characterized in that: In step (2), nuciferine- N -oxide and FeSO4·7H2O molar ratio is 1:2; the concentration of FeSO4·7H2O methanol solution is 1 mol / L; N -The ratio of oxide and saturated NaHCO3 solution is 1mmol:10mL;.

6. The preparation method according to claim 2 or 5, characterized in that: In step (2), the stirring reaction is carried out at room temperature for 12 hours; the reaction is continued for 20 minutes; and the eluent composed of chloroform: methanol: triethylamine in a volume ratio of 10:1:1‰ is used for elution.

7. The preparation method according to claim 2, characterized in that: In step (3), the molar ratio of proto-nuciferine, triethylamine and RX is 1:2-5:1-2.

8. The preparation method according to claim 2 or 7, characterized in that: In step (3), the stirring reaction is carried out at room temperature for 10-12 hours; and saturated sodium bicarbonate is used to quench the reaction.

9. Use of the nuciferine derivative as claimed in claim 1 in the preparation of uric acid-lowering or kidney-protecting drugs.

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