Delta6a, 7 nuciferine N-o-methylbenzene derivative as well as preparation method and application thereof

Abstract

The invention discloses a delta6a, 7 nuciferine N-o-methylbenzene derivative and a preparation method and application thereof.The chemical structure of the delta6a, 7 nuciferine N-o-methylbenzene derivative is shown in the formula I. In the formula I, an aromatic ring A is selected from a benzene ring, a naphthalene ring, biphenyl or nitrogen heteroaromatic ring; r is selected from an electron donating group or an electron withdrawing group. According to the invention, by adopting a metal palladium catalytic system and exploring different catalytic conditions, optimized conditions for synthesizing the delta6a, 7 nuciferine N-o-methylbenzene derivative are obtained. The delta6a, 7 nuciferine N-o-methylbenzene derivative disclosed by the invention has fat cell lipid accumulation inhibition activity, and has development potential in anti-obesity drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a kind of Δ 6a,7 N-ortho-methyl benzene derivative of nuciferine and its preparation method and application. BACKGROUND

[0002] For centuries, natural resources used in folk medicine to combat obesity and its related diseases, especially food resources, have been attracting increasing attention due to their low toxicity and mild adverse side effects. By ingeniously utilizing natural lipid-lowering active ingredients such as curcumin, Methyl Ganoderate, Echinocystic Acid, and Berberine, highly effective anti-obesity drugs with broad clinical application prospects and controllable side effects can be developed, showing great potential and hope in the commercial field. With the development of natural drugs, natural lipid-lowering compounds with fewer toxic and side effects have received extensive attention. Natural compounds such as polyphenols, flavonoids, saponins, terpenes, and alkaloids have good lipid-lowering activity. Screening compounds with high efficiency in inhibiting fat formation and reducing body weight from natural resources such as plants and microorganisms, optimizing the structure of natural products through chemical or microbial methods, and improving their inhibitory activity and bioavailability are important directions for future research.

[0003] Nuciferine is an aporphine alkaloid extracted from the dried leaves of Nymphaea tetragona Georgi Nelumbo nucifera Modern pharmacological studies have shown that nuciferine, the main active ingredient in lotus leaves, can significantly reduce body weight, serum total cholesterol (TC), and triglyceride (TG) levels in high-fat diet-induced obese mouse models, and effectively inhibit lipase activity to help reduce fat absorption. With continuous research on the pharmacological effects of nuciferine, it was found that it can activate the AMPK (adenosine monophosphate-activated protein kinase) signaling pathway, inhibit the expression of key enzymes such as FAS in fatty acid synthesis, and thus inhibit liver lipid synthesis. In recent years, with the progress of molecular biology technology, research has gradually focused on the mechanisms of nuciferine in regulating intestinal lipid absorption, lipid metabolism-related gene expression, and intestinal flora modulation, providing a more solid theoretical basis for its clinical application. Therefore, it is expected that molecular structure improvement of nuciferine will provide new strategies for the prevention and treatment of obesity and related metabolic diseases.

[0004] It should be noted that the information disclosed in the above background section is only used to enhance the understanding of the background of the present disclosure, and therefore can include information that does not constitute prior art known to those of ordinary skill in the art. SUMMARY

[0005] The purpose of the present invention is to provide a 6a,7 Nuciferine N-o-methylbenzene derivatives and their preparation methods and applications, the Δ 6a,7 N-o-methylbenzene derivatives of nuciferine have the activity of inhibiting lipid accumulation in adipocytes and have development potential in anti-obesity drugs.

[0006] In order to achieve the above object, the present invention provides a 6a,7 Nuciferine N-o-methylbenzene derivative, the Δ 6a,7 The chemical structure of nuciferine N-o-methylbenzene derivatives is shown in Formula I: In formula I, the aromatic ring A is selected from a benzene ring, a naphthalene ring, a biphenyl ring or a nitrogen aromatic heterocycle; and R is selected from an electron donating group or an electron withdrawing group.

[0007] Preferably, the electron-donating group is selected from methyl and methoxy; and the electron-withdrawing group is selected from halogen or trifluoromethyl.

[0008] Preferably, the electron withdrawing group is selected from bromine or trifluoromethyl.

[0009] Preferably, the Δ 6a,7 The chemical structure of the nuciferine N-o-methylbenzene derivative is selected from any one of the following: .

[0010] The second object of the present invention is to provide the Δ 6a,7 The preparation method of nuciferine N-o-methylbenzene derivatives, method 1 comprises: Pd(OAc)2 and BINAP were dissolved in dry toluene and stirred continuously at room temperature to ensure that the catalyst and ligand were fully dissolved and activated; then, under an inert atmosphere, demethyl nuciferine, a bromide compound as shown in formula II and t −BuOK, and heat the reaction mixture to 100 ~ 110 ° C to obtain the Δ 6a,7 Nuciferine N-o-methylbenzene derivatives; wherein the Pd(OAc)2, BINAP, t −The molar ratio of BuOK to demethylnuciferine is 0.15:0.3:1.8~2:1; Method 2 includes: CuI and NMI were dissolved in dry toluene and stirred continuously at room temperature to ensure that the catalyst and ligand were fully dissolved and activated; then, demethyl nuciferine, the bromide shown in formula II and t −BuOK, and heating the reaction mixture to 80 ~ 100 ° C to obtain the Δ 6a,7 Nuciferine N-o-methylbenzene derivatives; wherein the CuI, NMI, t The molar ratio of −BuOK to demethylnuciferine is 0.15:0.3:1.8~2:1.

[0011] Preferably, in method one and method two, the molar ratio of the bromide and demethylnuciferine is 2:1; or / and, in method one and method two, the ratio of the volume of toluene to the mass of demethylnuciferine is 2 mL:30 g; or / and, in method one and method two, after the reaction is completed, ethyl acetate is used for extraction, the organic phase is collected, dried, concentrated, and the product is obtained by separation and purification.

[0012] Preferably, the preparation method of demethylnuciferine comprises: dissolving nuciferine in dichloromethane, cooling the entire reaction solution to -20 ° C, and slowly adding m -CPBA in dichloromethane solution, continue stirring at low temperature, then move to room temperature and continue stirring. When the raw material is converted into the intermediate product nuciferine nitrogen oxide, the reaction solution is cooled to -20 ° C again, methanol is added, and FeSO4·7H2O is added to the reaction solution. Then, the mixture is continued to stir at low temperature, then moved to room temperature and stirred to react to obtain demethylnuciferine.

[0013] More preferably, the nuciferine and m The molar ratio of -CPBA and FeSO4·7H2O is 6.8:5.8:13.4; or / and the ratio of the mass of nuciferine to the volume of dichloromethane and methanol is 1 g:10 mL:12.5 mL.

[0014] The third object of the present invention is to provide the use of the N-aryl nuciferine derivatives in the preparation of anti-obesity drugs.

[0015] The fourth object of the present invention is to provide the use of the N-aryl nuciferine derivatives in the preparation of drugs for inhibiting lipid accumulation.

[0016] The present invention's Δ 6a,7 Nuciferine N-o-methylbenzene derivatives and their preparation methods and applications have the following advantages: The present invention adopts a metal palladium catalytic system and explores different catalytic conditions to obtain the synthesis of Δ 6a,7Optimum condition of N-o-methyl benzene derivative of nuciferine. The Δ 6a,7 N-o-methyl benzene derivative of nuciferine has adipocyte lipid accumulation inhibitory activity, and has development potential in anti-obesity drugs. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 Oil red O staining results in the determination of lipid-lowering activity in vitro of 3T3-L1 preadipocyte cell line of the present application.

[0018] Figure 2 Oil red O content in the determination of lipid-lowering activity in vitro of 3T3-L1 preadipocyte cell line of the present application. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0020] It should be noted that, in the examples, the specific conditions not specified are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The instruments used are all conventional products that can be obtained by market purchase, and the raw materials and reagents used are all market goods or can be prepared by known methods.

[0021] In the present application, all features defined in the form of numerical range or percentage range, such as numerical value, quantity, content and concentration, are only for the sake of brevity and convenience. Therefore, the description of numerical range or percentage range should be considered to have covered and specifically disclosed all possible sub-ranges and individual numerical values (including integers and fractions) within the range.

[0022] The features mentioned in the present application can be combined arbitrarily, as long as the combination of these features does not exist contradiction, all possible combinations should be considered as the scope disclosed in the specification. Each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless specifically stated, the disclosed features are only general examples of equivalent or similar features.

[0023] I. Preparation of N-normuciferine The nitrogen atom on the B ring of nuciferine is a tertiary amine. In order to carry out the subsequent C-N coupling reaction, the methyl group on the nitrogen atom must be removed first to prepare N-normuciferine. Nuciferine is first reacted with meta-chloroperbenzoic acid (m-CPBA) to obtain the first intermediate, the nitroxide of nuciferine. In view of the fact that meta-chloroperbenzoic acid (m-CPBA) is a strong oxidizing agent, the reaction is carried out in a solvent with low polarity, such as dichloromethane, and the reaction temperature is controlled at 0-5°C to avoid the side reaction of the double bond on the B ring of nuciferine. m -CPBA) reaction to obtain the first intermediate, the nitroxide of nuciferine. In view of the fact that meta-chloroperbenzoic acid (m-CPBA) is a strong oxidizing agent, the reaction is carried out in a solvent with low polarity, such as dichloromethane, and the reaction temperature is controlled at 0-5°C to avoid the side reaction of the double bond on the B ring of nuciferine.m -CPBA) will release a lot of heat energy during the oxidation reaction. To ensure the safety and controllability of the reaction, the reaction system needs to be cooled in advance. m A dichloromethane solution of -CPBA was slowly added dropwise to the reaction system to achieve nitrogen oxidation of nuciferine. The resulting nuciferine nitrogen oxide did not require further purification and could be used directly in subsequent reactions. Methanol and ferrous sulfate heptahydrate were added at low temperatures and the reaction was continued for 10 hours to successfully produce the demethylated product.

[0024] In this reaction, low temperature conditions are crucial because too high a temperature will lead to the formation of by-products, which will significantly reduce the yield. Through preliminary experimental exploration, it was found that under low temperature conditions of -20℃ and -10℃, the addition of m -CPBA, methanol and excess iron salt can give N-Nornuciferine in 45% yield.

[0025] Example 1 Dissolve nuciferine (2.0 g, 6.8 mmol) in 20 mL of dichloromethane solution in a 250 mL two-necked flask. Cool the entire reaction solution to -20 °C and slowly add m -CPBA (1.0 g, 5.8 mmol) in dichloromethane was stirred at low temperature for 20 min, then moved to room temperature and continued to stir while observing the reaction progress with a plate. When the raw material was converted into the intermediate product, nuciferine nitrogen oxide, the reaction solution was cooled to -20°C again, 25 mL of methanol was added, and FeSO4·7H2O (3.7 g, 13.4 mmol) was added to the reaction solution. Then, the mixture was stirred at low temperature for 40 min, moved to room temperature, and stirred for another 6 h. After TLC detection, saturated sodium thiosulfate solution was added to quench the reaction. The product was filtered through a suction filtration device and the residue was washed twice with ethyl acetate. The aqueous phase was then extracted with ethyl acetate 3-5 times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a dark green product. The product was dissolved again with a small amount of dichloromethane and slurried with a large amount of methanol. The pigment material was filtered out by suction filtration, and the filtrate was collected and concentrated under reduced pressure to obtain a dark yellow product. Silica gel column chromatography with a mobile phase of dichloromethane:methanol:aqueous ammonia = 15:1:0.2 (volume ratio) was used to separate and purify 0.9 g of N-demethylnuciferine as a yellow oil with a yield of 45%.

[0026] 2. Δ 6a,7 Optimization of Preparation Conditions of Nuciferine N-o-Methylbenzene Derivatives 1. Ligand selection Pd(OAc)2 (10 mol%) was used as catalyst, Johnphos, NiXantphos and CataCXiumA were used as ligands (20 mol%), demethylnuciferine (0.1 mmol) and o-methylbromobenzene (0.2 mmol) were used as substrates, and toluene (2 mL) was used as solvent. t -BuOK (1.5 mmol) was used as the base and the reaction was carried out at 110℃ for 12 h. No product was generated. The ligand was replaced with BINAP. t -BuOK reacted under alkaline conditions, and the results showed that two fluorescent spots with very close polarity appeared, and two of them showed color to potassium bismuth iodide. So under the conditions of Pd(OAc)2 as a catalyst, t -BuOK was used as a base in toluene solvent under a nitrogen atmosphere at 110°C for 8 h. Two products were obtained by column chromatography and chromatography silica gel preparation plate separation, and subsequent structural analysis was performed. By mass spectrometry analysis, the molecular weights of the two products were determined to be 371.1885 and 369.1729, respectively.

[0027] In order to further clarify the chemical structures of the two compounds, the H NMR ( 1 The compound with a molecular weight of 371.1885 was identified as the N-o-methylbenzene derivative of nuciferine (denoted as 2a), and the compound with a molecular weight of 369.1729 was identified as Δ 6a,7 The N-o-methylbenzene derivative of nuciferine (denoted as 3a), that is, the hydrogen at the C6a position and the hydrogen at the C7 position undergo an elimination reaction, thereby forming a unique dehydronuciferine derivative with a phenanthrene ring structure.

[0028] 2. Optimization of selective reaction conditions Based on the above reaction conditions, the effects of different catalysts, bases and solvents were also studied. It was found that different catalysts, bases and solvents would affect the reaction. When 1,4-dioxane was used as the solvent, no product was generated. When DMF and THF were used as the reaction solvents, the yields of compounds 2a and 3a were very low. Moreover, when the bases were selected as inorganic bases Cs2CO3, K2CO3 and CsF, as well as inorganic bases NaHMDS, the yields of compounds 2a and 3a were also very low. In order to further study the selectivity under different conditions, the yields of compounds 2a and 3a under different combinations of conditions were studied in toluene as the solvent, hoping to selectively obtain Δ 6a,7 Nuciferine N-o-methylbenzene derivative.

[0029] First, we tried to selectively modify the catalyst by re-screening it (see Table 1). Therefore, we considered screening palladium or copper catalysts in order to selectively avoid the formation of elimination products while ensuring the reaction proceeds. As shown in Table 1, in the copper-catalyzed reaction system, using CuI as catalyst, NMI as ligand, t When -BuOK is used as the base, a higher number of elimination products are selectively generated. In contrast, when CuBr is used as the catalyst, DMEDA as the ligand, and CH3ONa as the base, the reaction hardly occurs. Coupling on the secondary amine of nuciferine is also difficult when other palladium catalysts, such as PdCl2, Pd[P(ph)3]4, and (Ph3Pd)2Cl2, are used as catalysts.

[0030] Subsequently, they further explored a reaction system using Pd2(dba)3 as a catalyst and BINAP as a ligand, systematically screening various bases. They found that under weaker alkaline conditions, the reaction primarily produced the uneliminated product. Although the overall conversion rate decreased, this discovery achieved a certain degree of selective control over the reaction.

[0031] During the experiment, the temperature, the strength of the base and the eq. were carefully screened. Finally, when the temperature was raised to 110 °C and t When -BuOK was used as the base, the reaction showed a significant characteristic, that is, almost only the elimination product was generated. It was found that when the eq. of the base was 2.0 eq., Δ 6a,7 The yield of nuciferine N-o-methylbenzene derivatives is improved.

[0032] Table 1 Optimization of selective reaction conditions Note: a Proportion of generated products; b No product was detected; BINAP\Ph3P represents BINAP or Ph3P; NMI represents N-methylimidazole; DMEDA represents N,N'-dimethylethylenediamine.

[0033] In summary, the selective synthesis of Δ 6a,7 The optimal conditions for the synthesis of nuciferine N-o-methylbenzene derivatives are: nuciferine (1.0 eq.), aryl bromide (2.0 eq.), 15 mol% Pd(OAc)2 as catalyst, t -BuOK (2.0 eq.) was used as a base in toluene solvent under nitrogen atmosphere at 110°C for 8 hours.

[0034] 3. Δ 6a,7 Preparation of N-o-methylbenzene derivatives of nuciferine The present invention's Δ 6a,7 The general preparation method of nuciferine N-o-methylbenzene derivatives is as follows: In an oxygen-free environment of a glove box, Pd(OAc)2 (3.6 mg, 15 mol%) and BINAP (18 mg, 30 mol%) were dissolved in dry toluene (2 mL) and stirred at room temperature for two hours to ensure that the catalyst and ligand were fully dissolved and activated. Subsequently, demethyl nuciferine (30 mg, 0.1 mmol, 1.0 eq.), bromide (0.2 mmol, 2.0 eq.) and t -BuOK (22 mg, 0.2 mmol, 2.0 eq) was added, and the reaction mixture was heated to 100°C for 8 h. After completion of the reaction, the reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was collected, dried over Na2SO4, and concentrated under reduced pressure. The product was separated and purified by silica gel column chromatography.

[0035] Example 2 Compound 3a Yellow solid, yield 60%; 1 H NMR (600 MHz, CDCl3): d 9.48(d, J = 8.5 Hz, 1H), .37(d, J = 3.9 Hz, 2H), 7.36–7.33(m, 2H), 7.31(dd, J = 8.5, 4.3 Hz, 1H), 7.29–7.26(m,2H), 7.11(s, 1H), 6.05(s, 1H), 4.06(s, 3H), 3.93(s, 3H), 3.91–3.87(m, 1H),3.66(dt, J = 11.1, 4.6 Hz, 1H), 3.53(ddd, J = 16.1, 11.3, 5.2 Hz, 1H), 3.23(dt, J= 15.4, 3.7 Hz, 1H), 2.24(s, 3H) ppm; 13C NMR (150 MHz, CDCl3): δ 151.09, 145.91, 145.80, 140.98, 136.32, 134.68, 131.15, 129.33, 127.66, 127.61, 126.69, 126.38, 126.24, 126.20, 126.03, 124.48, 122.63, 119.10, 111.52, 103.54, 59.75, 56.44, 48.74, 31.78, 18.16 ppm; HRESIMS: calcd. for C 25 H 23 NO2[M + H]+: 370.1729, found: 370.1744.

[0036] Example 3 Compound 3b Yellow solid, yield 66%; 1 H NMR (600 MHz, CDCl3): d 9.48(d, J = 8.6 Hz, 1H), 7.44(dd, J = 7.9, 1.6 Hz, 1H), 7.40(ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.35–7.32(m, 1H),7.09(s, 1H), 6.98(s, 2H), 6.87(d, J = 1.9 Hz, 1H), 6.67(s, 1H), 4.05(s, 3H),3.92(s, 3H), 3.81(t, J = 5.9 Hz, 2H), 3.35–3.33(m, 2H), 2.36(s, 6H) ppm; 13 C NMR (150 MHz, CDCl3): d151.03, 147.79, 145.82, 141.66, 139.11, 134.35, 129.30,127.67, 126.68, 126.39, 126.22, 125.98, 124.87, 123.01, 122.96, 119.47,111.67, 105.31, 59.77, 56.44, 48.75, 31.44, 21.39 ppm; HRESIMS: calcd. for C 26 H 25 NO2[M + H] + : 384.1885, found: 384.1890.

[0037] Example 4 Compound 3e Yellow solid, yield 30%; 1 H NMR (600 MHz, CDCl3): δ 9.46 (d, J = 8.0 Hz, 1H), 7.41–7.39 (m, 1H), 7.37 (dd, J = 7.9, 1.3 Hz, 1H), 7.33–7.30 (m, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.09 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.46 (s, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.77 (t, J = 6.0 Hz, 2H), 3.36 (t, J = 6.0 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): 157.12, 151.08, 145.80, 142.59, 140.90, 134.48, 129.34, 127.67, 127.44, 126.72, 126.33, 125.99, 124.64, 122.81, 119.26, 114.89, 111.57, 104.31, 59.79, 56.46, 55.54, 49.21, 31.56 d ppm; HRESIMS: calcd. for C 25 H 23 NO3[M +H]+ :386.1678, found:386.1689.

[0038] Example 5 Compound 3w Yellow solid, yield 82%; 1 H NMR (600 MHz, CDCl3): d 1 H NMR (601M Hz, Chloro for m– d ) d 9.48(d, J = 8.6 Hz, 1H), 7.44(dd, J = 7.9, 1.6 Hz, 1H), 7.41–7.39(m, 1H),7.36–7.33(m, 2H), 7.10(s, 1H), 6.95(ddd, J = 7.9, 2.0, 0.9 Hz, 1H), 6.90(t, J =2.3 Hz, 1H), 6.77–6.75(m, 2H), 4.04(s, 3H), 3.92(s, 3H), 3.84(t, J = 5.9 Hz,2H), 3.82(s, 3H), 3.35(t, J = 6.0 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 160.65,151.06, 149.10, 145.80, 141.19, 134.21, 130.04, 129.20, 127.66, 126.73,126.49, 125.97, 125.05, 123.20, 119.42, 117.48, 111.70, 110.86, 109.83,105.77, 59.78, 56.43, 55.33, 48.60, 31.39 ppm; HRESIMS: calcd. for CIMS 25 H 23 NO3[M +H] + :386.1678, found:386.1689.

[0039] Example 6 Compound 3i Yellow solid, yield 60%;1 H NMR (600 MHz, CDCl3): d 9.46(d, J = 7.7 Hz, 1H), 8.36(d, J = 8.4 Hz, 1H), 8.01(d, J = 8.4 Hz, 1H), 7.50(ddd, J = 8.3, 6.7, 1.2 Hz, 1H),7.40(dd, J = 7.5, 5.6 Hz, 2H), 7.28(td, J = 6.0, 5.3, 2.8 Hz, 2H), 7.20(dd, J =6.8, 2.7 Hz, 1H), 7.15(s, 1H), 6.91(d, J = 8.0 Hz, 1H), 4.08(s, 3H), 4.07(s,3H), 4.00–3.96(m, 1H), 3.94(s, 3H), 3.78–3.75(m, 1H), 3.67–3.63(m, 1H), 3.31–3.27(m, 1H) ppm; 13 C NMR (150 MHz, CDCl3): d 154.19, 151.09, 145.85, 142.72,137.21, 134.68, 131.63, 129.39, 127.61, 126.87, 126.60, 126.26, 125.99,125.62, 124.31, 124.09, 123.71, 122.52, 122.49, 119.16, 111.57, 104.36,104.13, 59.78, 56.50, 55.67, 49.76, 31.90 ppm; HRES: calcd. for CIMS 29 H 25 NO3[M +H] + :436.1834, found:436.1865.

[0040] Example 7 Compound 3h Yellow solid, yield 50%; 1 H NMR (600 MHz, CDCl3): d 9.51(d, J= 7.6 Hz, 1H),7.67(d, J = 6.6 Hz, 2H), 7.64(s, 2H), 7.48(t, J = 1.9 Hz, 1H), 7.47(s, 1H), 7.44(d, J =3.9 Hz, 2H), 7.41–7.40 (m, 1H), 7.38–7.35(m, 2H), 7.12(s, 1H), 4.05(s, 3H),3.93(s, 3H), 3.90(d, J = 6.0 Hz, 2H), 3.38(t, J = 5.9 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 151.12, 147.06, 141.09, 140.67, 134.20, 129.20, 128.81, 128.06,127.70, 127.06, 126.87, 126.79, 126.50, 125.12, 123.29, 119.48, 111.77,105.84, 59.81, 56.46, 48.50, 31.40 ppm; HRESIMS: calcd. for C 30 H 25 NO2[M + H] + :found:432.1890.

[0041] Example 8 Compound 3f Yellow solid, yield 56%; 1 H NMR (600 MHz, CDCl3): d 9.48(d, J = 9.3 Hz, 1H), 7.40(dt, J = 5.9, 1.2 Hz, 2H), 7.36–7.33(m, 1H), 7.31(dd, J = 8.8, 4.9 Hz, 2H), 7.15(t, J = 8.5 Hz, 2H), 7.10(s, 1H), 6.48(s, 1H), 4.05(s, 3H), 3.92(d, J = 1.3 Hz,3H), 3.77(t, J= 6.0 Hz, 2H), 3.36(t, J = 5.6 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 160.75, 159.13, J CF = 243 Hz), 151.13, 145.80, 143.83, 143.81, J CF = 3 Hz), 141.96, 134.19, 129.16, 127.66, 127.50, 127.44, 126.79, 126.37, 125.97, 124.88, 123.15, 119.16, 116.42, 116.27, 111.63, 104.77, 60.19, 59.78, 56.41, 48.95, 31.43 ppm; HRESIMS: calcd. for C 24 H 20 FNO2[M + H] + : 374.1478, found: 374.1499.

[0042] Example 9 Compound 3g Yellow solid, yield 70%; 1 H NMR (600 MHz, CDCl3): d 9.50 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 - 7.42 (m, 1H), 7.40 - 7.38 (m, 1H), 7.37 - 7.34 (m, 1H), 7.12 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 7.10 (s, 1H), 7.04 (dt, J = 10.7, 2.3 Hz, 1H), 6.88 - 6.84 (m, 1H), 6.82 (s, 1H), 4.05 (s, 3H), 3.93 (s, 3H), 3.84 (t, J = 5.9 Hz, 2H), 3.34 (t, J = 5.5 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl3): d 162.81, 151.18,145.89, 140.43, 133.93, 130.37\130.31( J CF = 9 Hz), 129.03, 127.71, 126.85,126.62, 126.04, 125.45, 123.66, 120.16\120.14( J CF = 3 Hz), 119.42, 111.87,111.60\111.45( J CF = 38 Hz), 110.61\110.47( J CF = 21 Hz), 106.62, 59.81, 56.46,48.40, 31.23 ppm; HRESIMS: calcd. for C 24 H 20 FNO2[M + H] + :374.1478, found:374.1499.

[0043] Example 10 Compound 31 Yellow solid, yield 59%; 1 H NMR (600 MHz, CDCl3): d 9.49(d, J = 8.5 Hz, 1H), 7.55–7.52(m, 2H), 7.45–7.40(m, 2H), 7.37(ddd, J = 8.5, 6.6, 1.9 Hz, 1H), 7.23–7.20(m, 2H), 7.10(s, 1H), 6.70(s, 1H), 4.04(s, 3H), 3.92(s, 3H), 3.80(t, J = 5.9Hz, 2H), 3.35–3.32(m, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d151.22, 146.68, 145.91,140.40, 133.87, 132.54, 128.89, 127.70, 126.89, 126.62, 126.60, 126.01,125.44, 123.70, 119.27, 117.08, 111.87, 106.53, 59.80, 56.45, 48.64, 30.99ppm; HRESIMS: calcd. for C 24 H 20 BrNO 22 [M + H] + :434.3330, found:434.3355.

[0044] Example 11 Compound 3k Yellow solid, yield 52%; 1 H NMR (600 MHz, CDCl3): d 8.14(d, J = 8.4 Hz, 1H), 7.56(s, 2H), 7.54(d, J = 8.4 Hz, 1H), 7.03(s, 1H), 5.57(q, J = 7.2 Hz, 1H), 5.50(d, J = 4.8 Hz, 1H), 3.75(s, 1H), 3.17(dd, J = 16.8, 4.8 Hz, 1H), 3.13(dd, J = 16.8, 1.8Hz, 1H), 2.40(s, 6H), 2.30(d, J = 16.2 Hz, 1H), 2.25(d, J = 16.8 Hz, 1H), 1.78(d, J = 6.6 Hz, 3H), 1.54(s, 3H) ppm; 13 C NMR (150 MHz, CDCl3): d151.18, 149.24,145.87, 140.49, 133.90, 130.57, 129.00, 127.70, 127.56, 126.85, 126.80,126.62, 126.01, 125.43, 123.65, 123.50, 122.93, 119.34, 111.85, 106.48,59.81, 56.44, 48.39, 31.25 ppm; HRESIMS: calcd. for C 24 H 20 BrNO2[M + H] + :434.3330,found:434.3355.

[0045] Example 12 Compound 3m Yellow solid, yield 40%; 1 H NMR (600 MHz, CDCl3): d 9.48(d, J = 8.5 Hz, 1H), 7.44(t, J = 7.7 Hz, 2H), 7.40(dd, J = 12.9, 6.2 Hz, 2H), 7.35(d, J = 8.1 Hz, 2H), 7.34–7.32(m, 1H), 7.22–7.19(m, 1H), 7.10(s, 1H), 6.68(s, 1H), 4.05(s, 3H), 3.92(s,3H), 3.84(t, J = 5.9 Hz, 2H), 3.36(t, J = 5.9 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 151.20, 147.62, 145.93, 134.14, 129.56, 129.11, 127.73, 126.84, 126.64,126.05, 125.29, 125.24, 124.66, 123.45, 119.43, 111.83, 106.22, 59.85, 56.51,48.90, 31.12 ppm; HRESIMS: calcd. for C 25 H 21 N2O4[M + H]+ :363.2073, found:363.2078.

[0046] Example 13 Compound 3p Yellow solid, yield 40%; 1 H NMR (600 MHz, CDCl3): d 9.52(d, J = 8.4 Hz, 1H), 7.63(d, J = 8.4 Hz, 2H), 7.49(dd, J = 7.8, 1.7 Hz, 1H), 7.46–7.44(m, 1H), 7.43–7.40(m, 2H), 7.40(s, 1H), 7.12(s, 1H), 6.95(s, 1H), 4.05(s, 3H), 3.93(s, 3H),3.91(t, J = 5.9 Hz, 2H), 3.33(t, J = 5.9 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 151.26, 145.94, 139.54, 133.67, 128.93, 127.76, 126.95, 126.73, 126.55\126.53( J CF = 3 Hz), 126.09, 125.86, 124.09, 123.28, 119.52, 112.01, 107.79, 59.85,56.48, 47.97, 31.15 ppm; HRESIMS: calcd. for C 25 H 20 F3NO2[M + H] + :423.1446, found:423.1461.

[0047] Example 14 Compound 3o Yellow solid, yield 35%; 1 H NMR (600 MHz, CDCl3): d 9.51(d, J= 8.4 Hz, 1H), 7.58(s, 1H), 7.54–7.50(m, 2H), 7.46–7.42(m, 2H), 7.42–7.40(m, 1H), 7.40–7.38(m,1H), 7.12(s, 1H), 6.76(s, 1H), 4.05(s, 3H), 3.93(s, 3H), 3.89–3.87(m, 2H),3.36(t, J = 5.4 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 151.26, 148.32, 145.94,140.37, 133.82, 132.11, 131.89, 129.83, 128.96, 127.95, 127.73, 126.90,126.63, 126.08, 125.56, 123.79, 121.20, 120.23, 119.35, 111.93, 106.42,59.82, 56.46, 48.29, 31.26 ppm; HRESIMS: calcd. for C 25 H 20 F3NO2[M + H] + :423.1446,found:423.1461.

[0048] Example 15 Compound 3 J Yellow solid, yield 60%; 1 H NMR (600 MHz, CDCl3): d 9.51(d, J = 8.6 Hz, 1H), 7.46(ddd, J = 7.9, 1.9, 0.6 Hz, 1H), 7.44(dd, J = 6.6, 1.3 Hz, 1H), 7.43–7.41(m, 2H),7.40–7.37(m, 1H), 7.31–7.29(m, 2H), 7.12(s, 1H), 6.69(s, 1H), 4.07(s, 3H),3.94(s, 3H), 3.84–3.82(m, 2H), 3.37(ddd, J = 6.6, 5.4, 1.0 Hz, 2H). ppm; 13C NMR (150 MHz, CDCl3): δ 151.20, 146.41, 141.05, 134.05, 129.60, 129.31, 129.07,127.71, 126.86, 126.50, 126.44, 126.05, 125.23, 123.46, 111.83, 105.75, 59.81, 56.48, 48.55, 31.33 ppm. HRESIMS: calcd. for C 24 H 20 ClNO2[M + H]+: 390.8790, found: 390.8882.

[0049] Example 16 Compound 3u Yellow solid, yield 70%; 1 H NMR (600 MHz, CDCl3): d 9.47(d, J = 8.6 Hz, 1H), 7.48(dd, J = 7.8, 1.7 Hz, 1H), 7.39–7.37(m, 1H), 7.36–7.35(m, 2H), 7.33(dd, J = 7.4,1.7 Hz, 1H), 7.30(td, J = 5.6, 2.7 Hz, 1H), 7.25(d, J = 1.5 Hz, 1H), 7.11(s, 1H), 6.03(s, 1H), 4.06(s, 3H), 3.93(s, 3H), 3.87(dd, J = 11.9, 4.4 Hz, 1H), 3.60–3.54(m, 2H), 3.34–3.30(m, 1H), 3.25–3.21(m, 1H), 1.18(dd, J = 15.5, 6.9 Hz, 6H)ppm; 13 C NMR (150 MHz, CDCl3): d151.06, 147.27, 145.75, 144.86, 142.32, 134.65,129.31, 127.64, 127.52, 127.22, 127.13, 126.79, 126.70, 126.18, 125.94,124.30, 122.53, 118.97, 111.41, 103.70, 59.76, 56.43, 49.34, 31.51, 27.66,24.60, 22.85 ppm; HRESIMS: calcd. for C 25 H 25 N2[M + H] + :398.2042, found:398.2053.

[0050] Example 17 Compound 3x Yellow solid, yield 76%; 1 H NMR (600 MHz, CDCl3): d 9.50(d, J = 8.4 Hz, 1H), 7.46(d, J = 1.8 Hz, 1H), 7.44–7.43(m, 2H), 7.42–7.40(m, 1H), 7.39(d, J = 2.0 Hz, 1H),7.37–7.32(m, 3H), 7.10(s, 1H), 7.01–6.96(m, 2H), 6.84(dd, J = 8.4, 2.4 Hz, 1H),6.77(s, 1H), 5.08(s, 2H), 4.05(s, 3H), 3.93(s, 3H), 3.83(t, J = 5.9 Hz, 2H),3.35(t, J = 5.9 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d159.83, 151.06, 149.09,145.80, 141.10, 136.87, 134.18, 130.05, 129.19, 128.57, 127.97, 127.64,127.52, 126.72, 126.55, 125.97, 125.07, 123.23, 119.42, 117.70, 111.70,110.65, 105.85, 70.05, 59.78, 56.42, 48.57, 31.37 ppm; HRES: calcd. forCIMS 31 H 27 NO3[M + H] + :462.1991, found:462.1999.

[0051] Example 18 Compound 3n Yellow solid, yield 68%; 1 H NMR (600 MHz, CDCl3): d 9.51(d, J = 8.6 Hz, 1H), 7.46(dt, J = 8.0, 6.8 Hz, 3H), 7.42(ddd, J = 7.9, 5.6, 1.6 Hz, 1H), 7.37(ddt, J = 9.2,6.7, 1.7 Hz, 3H), 7.24(t, J = 7.4 Hz, 1H), 7.13(s, 1H), 6.72(s, 1H), 4.07(s,3H), 3.95(s, 3H), 3.87(t, J = 6.0 Hz, 2H), 3.38(t, J = 6.0 Hz, 2H) ppm; 13 C NMR (150MHz, CDCl3): d151.07, 147.82, 145.81, 141.47, 134.24, 129.48, 129.26, 127.67,126.74, 126.43, 126.00, 125.29, 124.99, 124.34, 123.13, 119.41, 111.68,105.31, 59.79, 56.44, 48.56, 31.44 ppm; HRESIMS: calcd. for C 24 H 21 NO2[M + H] + :356.1572, found:356.1588.

[0052] Example 19 Compound 3r Yellow solid, yield 36%; 1 H NMR (600 MHz, CDCl3): d 89.51(d, J = 8.2 Hz, 1H), 8.64(s, 1H), 8.38(s, 1H), 7.76(d, J = 8.5 Hz, 1H), 7.48–7.44(m, 2H), 7.43(d, J = 8.8Hz, 2H), 7.12(s, 1H), 6.80(s, 1H), 4.05(s, 3H), 3.93(s, 3H), 3.89(t, J = 5.9 Hz, 2H), 3.35(t, J = 5.9 Hz, 2H) ppm; 13 C NMR (150 MHz, CDCl3): d 151.35, 145.87, 144.26,142.41, 139.55, 133.46, 132.35, 128.76, 127.73, 127.01, 126.74, 126.07,125.86, 124.47, 124.20, 119.12, 111.95, 107.09, 59.83, 56.41, 47.97, 31.07ppm; HRESIMS: calcd. for C 23 H 20 N2O2[M + H] + :359.1681, found:359.1697.

[0053] Four, Δ 6a,7 Evaluation of Lipid-lowering Activity of N-ortho-methylbenzene Derivatives of Nuciferine To systematically evaluate Δ 6a,7 To evaluate the lipid-lowering activity of N-ortho-methylbenzene derivatives of Nuciferine, the inhibitory efficiency of the derivatives on pancreatic lipase was quantitatively analyzed, and the binding mode of the active molecules with the active site of lipase was analyzed using molecular docking technology, with a focus on predicting the key hydrogen bond interactions and hydrophobic interactions. Secondly, using the 3T3-L1 preadipocyte differentiation model, the inhibitory effect of the derivatives on lipid accumulation was evaluated by analyzing the inhibition rate of lipid droplet formation through oil red O staining. In addition, the MTT method was used to evaluate the cell proliferation activity to verify the concentration range of the lipid-lowering activity of the target compounds. This provides innovative experimental evidence for the study of the structure-activity relationship of Nuciferine derivatives and the exploration of the lipid-lowering mechanism.

[0054] 1. In vitro lipase activity inhibition experiment Lipase enzyme activity is an important indicator for evaluating the anti-obesity effect of drugs, so the lipase inhibition capacity of N- Nuciferine derivatives was determined. Orlistat was used as a positive control for the preliminary screening of these derivatives at a concentration of 200 μM, as follows:

[0055] 5 mg of lipase was dissolved in 0.1 mol / L phosphate buffer (pH 7.4) to prepare a solution with a concentration of 0.71 mg / mL, which was stored at 4°C for later use. Then, the inhibitors (Nuciferine and its derivatives) were dissolved in DMSO to prepare a series of inhibitor solutions with different concentrations, while ensuring that the concentration of DMSO in the final solution was maintained at 3.0%. Then, they were immediately mixed with the lipase solution and reacted for 10 min at a constant temperature of 37°C, followed by the addition of 0.5 mmol / L NPP solution. After the reaction started, the absorbance value at 420 nm was measured using a spectrophotometer, denoted as A 0 . After waiting for 15 minutes for the reaction to proceed, the absorbance value was measured again, denoted as A t . To obtain accurate enzyme activity data, the absorbance before and after the reaction without the sample solution was measured as a control, and the entire experiment was performed in triplicate to ensure the repeatability and accuracy of the data, with the calculation formula as follows.

[0056] Inhibition rate% where A 0 : initial absorbance value of the reaction; A t : absorbance value after 15 min of reaction; ΔA1 : difference between before and after reaction with different concentrations of sample solution (A t - A 0)1; △A2: The difference between the reaction before and after without sample solution (A t - A 0 )2.

[0057] As shown in Table 2, the results show that most of the Δ 6a,7 The anti-lipase activity of N-o-methylbenzene derivatives of nuciferine was significantly reduced and failed to show obvious inhibitory activity. A few aromatic substituted derivatives such as compounds 3e, 3h, 3i, 3n, 3r, and 3w showed lower activity.

[0058] Table 2 Δ 6a,7 Inhibitory activity of nuciferine N-o-methylbenzene derivatives on pancreatic lipase The IC of compound 3x against lipase was further determined. 50 value, IC 50 =0.14655±0.006 mg / mL, which is better than nuciferine (IC 50 =0.208±0.02 mg / mL).

[0059] 2. In vitro cell proliferation activity assay of 3T3-L1 cell line 3T3-L1 preadipocytes were pretreated with 20 μM of the test compound, and the cell viability was measured for subsequent lipid-lowering activity evaluation as follows: (1) Cell recovery: Preparation: Preheat a water bath to 37°C, preheat complete culture medium for 3T3-L1 cells, quickly thaw cells frozen in liquid nitrogen or at -80°C, and shake to thaw in a 37°C water bath for 1-2 minutes. Transfer the suspension to a centrifuge tube containing preheated culture medium, add 2 mL of culture medium, centrifuge at low speed (800-1000 rpm, 5 minutes), and discard the supernatant. Resuspend the cells in 1 mL of culture medium and gently pipette to mix. Inoculate into a culture flask containing 4-5 mL of culture medium and adjust the density. Culture in a 37°C, 5% CO2 incubator, change the medium the next day, and continue culturing until the cells recover to normal before passage.

[0060] (2) Cell passaging: When the cells in the culture flask grow to about 80-90%, the passaging operation can be carried out. Preparation: Ensure a sterile operating environment, place the required sterile culture flasks, centrifuge tubes, pipettes, etc. in the clean bench, and irradiate with ultraviolet light for 30 minutes for disinfection. Observe the cell morphology and density under an inverted microscope. When the cells reach the appropriate passaging condition, the passaging experiment can be started. Digestion of cells (for adherent cells) Disinfect the mouth of the culture flask with 75% alcohol and remove the old culture medium. Wash the cells with PBS buffer to remove the residual culture medium. After addition, add trypsin containing 25% EDTA to digest the cells for 1-2 minutes (digestion time depends on the cell type). Usually, digestion is stopped when the cells become round and the gaps between them increase under the microscope. Add fresh culture medium containing serum to stop digestion and gently blow the cells to suspend them. Centrifuge the cell suspension at 1000 rpm for 5 minutes. Remove the supernatant and retain the cell pellet. Add an appropriate amount of complete culture medium 4-5 mL to the cell pellet and mix it by blowing to ensure that the cells are evenly dispersed. Based on the experimental requirements, divide the cell suspension into new culture flasks in appropriate proportions, add fresh culture medium, and label with the cell name, passage number, date, and operator. Return the culture flasks to the CO2 incubator and set the appropriate temperature, humidity, and CO2 concentration.

[0061] (3) Cell proliferation activity assay: The MTT assay was used to assay the in vitro cell proliferation activity of the compounds. 3T3-L1 cells were cultured in a 37°C, 5% CO2 incubator using a dedicated culture medium until the logarithmic growth phase. The test compound was diluted to 50 μM with DMSO and then used for further dilution. 5×10³ cells / well were seeded into a 96-well plate (100 μL / well). The test group: added the test sample (20 μM, 100 μL), the blank group: added blank culture medium (100 μL), and the control group: added culture medium containing 1‰ DMSO (100 μL). Each group had 3 replicates. After 24 h of incubation, 20 μL (5 mg / mL MTT solution) was added to each well and the culture was continued for 4 h. The supernatant was discarded, 150 μL DMSO / well was added, and the mixture was shaken for 10 min. The absorbance at 492 nm was measured using a microplate reader.

[0062] As shown in Table 3, the in vitro antiproliferative activity of compounds 3a~3x on 3T3-L1 preadipocytes was evaluated. As shown in Table 3, most compounds showed low toxicity at 20 μM, demonstrating that the compounds did not cause significant damage to 3T3-L1 preadipocytes, ensuring the normal progress of subsequent lipid-lowering activity experiments.

[0063] Table 3 Proliferative activity of compounds 3a~3x at 20 μM on 3T3-L1 cells 3. In vitro lipid-lowering activity assay of 3T3-L1 preadipocyte cell line After preliminary proliferation activity screening, compounds with less cell inhibitory activity were selected for in vitro lipid accumulation activity assay in 3T3-L1 preadipocytes, as follows: (1) Preparation of 3T3-L1 (mouse embryonic fibroblast) adipogenic differentiation medium: Thaw the serum at 4°C until completely thawed; Thaw each additive at room temperature until completely thawed, and gently shake A ① , B mix; A ② Centrifuge briefly to collect all the reagents at the bottom of the tube. ① 、A ② Add to basal medium A in sequence; mix thoroughly, label, and use. Solution B preparation: Add FBS (two FBS bottles are the same) and B to basal medium B in sequence, mix thoroughly, label, and use.

[0064] (2) Cell adipogenic differentiation: When the cell confluence reaches 80-90%, digest with 0.25% trypsin and count. The cell count is 2-3×10 4 cells / cm 2 Cells were seeded at a high density into 24-well plates (2 mL of complete medium per well) and incubated at 37°C, 5% CO2. When confluency reached 100%, the complete medium was aspirated and 2 mL of a mixture of 20 μM derivative compound and Induction Medium A was added. Induction was continued for 2-3 days. The cells were then switched to 2 mL of Induction Medium B for 1 day. After alternating between Induction Medium A and Medium B for 3-5 cycles, when sufficient lipid droplets were observed within the stem cells, the cells were cultured in Medium B for another 3-6 days until the lipid droplets became sufficiently large and plump. Induction was terminated, and the cells were then stained and subsequently identified.

[0065] (3) Oil Red O staining: After the adipogenic induction experiment, remove the induction medium and rinse with 1× PBS 1-2 times. Add 4% neutral formaldehyde to fix the cells for 30 minutes. During the fixation period, prepare Oil Red O working solution (saturated Oil Red O: distilled water = 3:2, filtered to remove impurities). Remove the aldehyde fixation solution and rinse with 1× PBS 1-2 times. Add 1 mL of Oil Red O working solution to each well and stain at room temperature for 30 minutes. Taking a six-well plate as an example, add 1 mL of Oil Red O working solution to each well and stain at room temperature for 30 minutes. Remove the Oil Red O working solution and rinse with 1× PBS 1-2 times to clean the background impurities. Then observe the induction and staining effects under a microscope.

[0066] like Figure 1 and Figure 2 (CG in the figure represents blank control) was added with 20 μM Δ 6a,7 When cells were treated with N-arylated nuciferine derivatives for 7 days, Δ 6a,7Compounds such as N-arylated nuciferine derivatives 3p, 3w, 3a, 3e, 3x and 3h all showed inhibitory effects on lipid accumulation during differentiation in 3T3-L1 preadipocytes to varying degrees.

[0067] Although the present invention has been described in detail through the above preferred embodiments, it should be understood that the above description is not intended to limit the present invention. After reading the above description, various modifications and substitutions of the present invention will become apparent to those skilled in the art. Therefore, the scope of protection of the present invention should be defined by the appended claims.

Claims

1. A Δ 6a,7 The nuciferine N-o-methylbenzene derivative is characterized by: The Δ 6a,7 The chemical structure of nuciferine N-o-methylbenzene derivatives is shown in Formula I: In formula I, the aromatic ring A is selected from a benzene ring, a naphthalene ring, a biphenyl ring or a nitrogen aromatic heterocycle; R is selected from an electron donating group or an electron withdrawing group.

2. The Δ according to claim 1 6a,7 The nuciferine N-o-methylbenzene derivative is characterized by: The electron-donating group is selected from methyl and methoxy; the electron-withdrawing group is selected from halogen or trifluoromethyl.

3. The Δ according to claim 2 6a,7 The nuciferine N-o-methylbenzene derivative is characterized by: The electron withdrawing group is selected from bromine or trifluoromethyl.

4. The Δ according to claim 1 6a,7 The nuciferine N-o-methylbenzene derivative is characterized by: The Δ 6a,7 The chemical structure of the nuciferine N-o-methylbenzene derivative is selected from any one of the following: 。 5. The Δ according to any one of claims 1 to 4 6a,7 The preparation method of nuciferine N-o-methylbenzene derivative is characterized by: Method 1 includes: Pd(OAc)2 and BINAP were dissolved in dry toluene and stirred continuously at room temperature to ensure that the catalyst and ligand were fully dissolved and activated; Subsequently, under an inert atmosphere, demethyl nuciferine, a bromide as shown in formula II and t −BuOK, and heat the reaction mixture to 100 ~ 110 ° C to obtain the Δ 6a,7 Nuciferine N-o-methylbenzene derivative; Wherein, the Pd(OAc)2, BINAP, t −The molar ratio of BuOK to demethylnuciferine is 0.15:0.3:1.8~2:1; Alternatively, method two includes: CuI and NMI were dissolved in dry toluene and stirred continuously at room temperature to ensure that the catalyst and ligand were fully dissolved and activated; then, demethyl nuciferine, the bromide shown in formula II and t −BuOK, and heating the reaction mixture to 80 ~ 100 ° C to obtain the Δ 6a,7 Nuciferine N-o-methylbenzene derivative; Wherein, the CuI, NMI, t The molar ratio of −BuOK to demethylnuciferine is 0.15:0.3:1.8~2:

1.

6. The preparation method according to claim 5, characterized in that In the method 1 and the method 2, the molar ratio of the bromide to demethylnuciferine is 2:1; Or / and, in the method 1 and the method 2, the ratio of the volume of the toluene to the mass of the demethylnuciferine is 2 mL:30 g; Or / and, in the method 1 and the method 2, after the reaction is completed, ethyl acetate is used for extraction, the organic phase is collected, dried, concentrated, and the product is obtained by separation and purification.

7. The preparation method according to claim 5, characterized in that The preparation method of demethylnuciferine comprises: Dissolve nuciferine in dichloromethane, cool the entire reaction solution to -20 °C, and slowly add m -CPBA in dichloromethane solution, continue stirring at low temperature, then move to room temperature and continue stirring. When the raw material is converted into the intermediate product nuciferine nitrogen oxide, the reaction solution is cooled to -20 ° C again, methanol is added, and FeSO4·7H2O is added to the reaction solution. Then, the mixture is continued to stir at low temperature, then moved to room temperature and stirred to react to obtain demethylnuciferine.

8. The preparation method according to claim 7, characterized in that The nuciferine m -The molar ratio of CPBA and FeSO4·7H2O is 6.8:5.8:13.4; Or / and, the ratio of the mass of the nuciferine to the volume of dichloromethane and methanol is 1 g:10 mL:12.5 mL.

9. Use of the N-aryl nuciferine derivative according to any one of claims 1 to 4 in the preparation of anti-obesity drugs.

10. Use of the N-aryl nuciferine derivative according to any one of claims 1 to 4 in the preparation of a drug for inhibiting lipid accumulation.

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