Malabaricone A and analogue thereof, preparation method and application of Malabaricone A in resisting MRSA (Methicillin Resistant Staphylococcus Aureus)
By synthesizing Malabaricone A and its analogues, the problem of MRSA resistance was solved, efficient and low-cost antibacterial drug preparation was achieved, and good antibacterial effect and safety were demonstrated.
Patent Information
- Application Number
- CN202510706920.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-29
- Publication Date
- 2025-09-23
AI Technical Summary
The existing antibiotics have a high resistance rate against Staphylococcus aureus, especially multidrug-resistant Staphylococcus aureus (MRSA) infection is serious, and there is a lack of effective new antibacterial drugs.
Malabaricone A and its analogs were synthesized, and a series of compounds were prepared through a modular synthesis strategy. Specific catalysts and reaction conditions were used to achieve high-yield and low-cost compound preparation for the treatment of MRSA infections.
Malabaricone A and its analogues showed significant anti-MRSA activity in vitro and in vivo, with MIC values lower than those of existing antibiotics and low toxicity to mammalian cells, showing good safety and development potential.
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Figure CN120682091A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of antibacterial drugs, and in particular relates to the application of Malabaricone A compounds and analogs thereof in drugs for resisting methicillin-resistant Staphylococcus aureus infection. Background Art
[0002] With the widespread use of antimicrobial drugs, the resistance rate of Staphylococcus aureus to first-line antibiotics such as β-lactams has exceeded 90%, and the minimum inhibitory concentration (MIC) of vancomycin against this bacterium has continued to rise, creating a serious bacterial resistance situation. Furthermore, multidrug-resistant Staphylococcus aureus (MRSA) accounts for 35%-50% of hospital-acquired infections worldwide, with detection rates exceeding 60% in ICU wards in China. There is an urgent need to develop new anti-MRSA drugs. Summary of the Invention
[0003] Based on the research findings of the present invention, the present invention provides Malabaricone A and its analogs, the structures of which are shown in Formula I:
[0004]
[0005] R is H or F, n=4, 5, 6, 7, 8.
[0006] Furthermore, R is F, and n=6.
[0007] The present invention also discloses the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-MRSA drug, wherein the use includes use as a therapeutic drug for treating MRSA infection alone or in combination with other drugs.
[0008] The present invention also provides a method for synthesizing Malabaricone A and its analogs, which comprises:
[0009] Step 1: Under the protection of inert gas and the presence of a catalyst, bromic acid as a raw material reacts with aryl magnesium bromide to prepare an aryl carboxylic acid; the catalyst is selected from ferric acetylacetonate; the bromic acid is 9-bromononanoic acid, 7-bromoheptanoic acid, 8-bromooctanoic acid, 10-bromodecanoic acid or 11-bromodecaneic acid;
[0010] Step 2: Under alkaline conditions and in the presence of a condensing agent and a protecting agent, the aryl carboxylic acid obtained in step 1 is reacted to prepare an N,O-dimethyl-protected aryl carboxylic acid; the condensing agent is selected from N,N-carbonyldiimidazole; and the protecting agent is selected from N,O-dimethylhydroxylamine hydrochloride;
[0011] Step 3: Under the protection of an inert gas and in the presence of an activating reagent, the N,O-dimethyl-protected aryl carboxylic acid obtained in step 2 reacts with 2,6-dimethoxybromobenzene to achieve debromination coupling between the carbonyl carbon atom and the aryl carbon atom; the activating reagent is n-butyl lithium;
[0012] Step 4: Under inert gas protection and ice bath conditions, the product obtained in step 3 reacts with boron tribromide to remove the methyl group in the methoxy group to obtain Malabaricone A and its analogs.
[0013] An optional solution is that the catalyst in step 1 is a catalytic system consisting of ferric acetylacetonate, hexamethylenetetramine and N,N,N,N-tetramethylethylenediamine.
[0014] Alternatively, the arylmagnesium bromide is phenylmagnesium bromide or 4-fluorophenylmagnesium bromide.
[0015] Alternatively, step 3 may include:
[0016] 3.1 Dissolve the product of step 2 in an organic solvent under inert gas protection;
[0017] 3.2 Under inert gas protection and -80 to -75°C, 2,6-dimethoxybromobenzene is dissolved in an organic solvent and n-butyl lithium is added dropwise;
[0018] 3.3 Under inert gas protection, add the mixed solution of step 3.1 dropwise to the mixed solution of step 3.2, react at -80 to -75°C, then heat to room temperature and continue the reaction.
[0019] The synthetic method of the present invention has the following significant advantages: (1) a modular synthetic strategy is adopted, and the yield of key steps reaches more than 90%; (2) compared with the extraction process, the chemical synthesis operation steps are simple; (3) the raw material cost is reduced to 1 / 20 of that of the extraction method; (4) a series of new derivatives can be obtained by targeted modification. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 is the nuclear magnetic resonance spectrum of the compound of Example 1 of the present invention;
[0021] Figure 2 is the nuclear magnetic resonance spectrum of the compound of Example 2 of the present invention;
[0022] Figure 3 is the nuclear magnetic resonance spectrum of the compound of Example 3 of the present invention;
[0023] Figure 4 is the nuclear magnetic resonance spectrum of the compound of Example 4 of the present invention;
[0024] Figure 5 is the nuclear magnetic resonance spectrum of the compound of Example 5 of the present invention;
[0025] Figure 6 is the nuclear magnetic resonance spectrum of the compound of Example 6 of the present invention;
[0026] Figure 7 The in vitro anti-MRSA activity test results of the compound of Example 1 are shown. The MIC in the figure represents the minimum inhibitory concentration of the compound against bacteria.
[0027] Figure 8 The electron microscopic observation results of the effect of the compound in Example 1 on bacterial morphology; the original magnifications were 15,000 times (AC, A is the blank control group, B is the 1 μg / ml compound treatment group, C is the 4 μg / ml compound treatment group) and 30,000 times (DF, D is the blank control group, E is the 1 μg / ml compound treatment group, F is the 4 μg / ml compound treatment group).
[0028] Figure 9 The in vivo anti-MRSA activity test results of the compound of Example 1;
[0029] Figure 10 The following are the results of cytotoxicity tests of the compound of Example 1 (n=5); (A) Cell viability of human intestinal epithelial cells (HIEC) after treatment with different concentrations of the compound of Example 1 for 24 h; (B) Cell viability of mouse brain microvascular endothelial cells (Bend.3) after treatment with different concentrations of the compound of Example 1 for 24 h; (C) Cell viability of mouse cardiomyocytes (HL-1) after treatment with different concentrations of the compound of Example 1 for 24 h; (D) Cell viability of human non-small cell lung cancer cells (A549) after treatment with different concentrations of the compound of Example 1 for 24 h. DETAILED DESCRIPTION
[0030] Unless otherwise specified, the scientific and technical terms used herein are understood according to the knowledge of ordinary technicians in the relevant fields.
[0031] The synthetic route of Malabaricone A and its analogs of the present invention is shown in Formula II:
[0032]
[0033] The following are specific examples of the present invention to further illustrate the present invention. The raw materials and reagents used in the following examples were purchased from Anaiji Chemical.
[0034] Example 1: Total Synthesis of Malabaricone A
[0035] Step 1: Under argon protection, using anhydrous tetrahydrofuran (THF) as solvent, 9-bromononanoic acid (4.72 g, 20.0 mmol) and the catalyst system iron acetylacetonate (Fe(acac), 0.36 g, 5 mol%), hexamethylenetetramine (HMTA, 0.14 g, 5 mol%) and N,N,N,N-tetramethylethylenediamine (TMEDA, 0.23 g, 10 mol%) were added to a reaction bottle containing 40 mL of THF, and then the reaction bottle was transferred to an ice-water bath and stirred for 10 minutes; then, 12.5 mL of phenylmagnesium bromide (2 M MgBr) was added dropwise to the reaction bottle. After the addition was complete, the reaction temperature was raised to room temperature and stirred for 12 h. After the reaction was complete, HCl (40 mL, 1 M) was slowly added to the reaction solution to quench the reaction. The reaction mixture was extracted with ethyl acetate (3×30 mL). The organic phases were combined and then washed with saturated NaCl water and dried over anhydrous Na2SO4. The oily residue after removing the solvent by rotary evaporation was purified by column chromatography (silica gel column 200-300 mesh, PE:EA=8:1) to obtain 4.31 g of colorless oily product 2 with a yield of 92%.
[0036] Step 2: The product 2 (2.34 g, 10 mmol) from the previous step was dissolved in 30 mL of dichloromethane (DCM). A condensing agent, N,N-carbonyldiimidazole (CDI, 2.43 g, 15 mmol), was added. After stirring for 20 min, triethylamine (TEA, 2.1 mL, 15 mmol, to provide an alkaline environment) and a protective reagent, N,O-dimethylhydroxylamine hydrochloride (CHNO·HCl, 1.46 g, 15 mmol), were added and reacted for 6 h. After completion of the reaction, HCl (30 mL, 1 M) was added to quench the reaction. The reaction mixture was extracted with DCM (3 × 30 mL). The organic phases were combined, washed with saturated NaCl water, dried over anhydrous Na2SO4, and the solvent was removed by rotary evaporation. The oily residue was separated by column chromatography (silica gel column 200-300 mesh, PE:EA = 5:1) to obtain the colorless oily product 3 (2.55 g, 92% yield).
[0037] Step 3: Under argon protection, the product 3 (1.663 g, 6 mmol) of the previous step was dissolved in 10 mL of THF for later use; in another dry reaction bottle, 2,6-dimethoxybromobenzene (1.302 g, 6 mmol) and 15 mL of THF were added under argon protection, and then the reaction bottle was transferred to a low-temperature reaction bath at -78 ° C and stirred for 10 min; n-butyl lithium ( nBuLi, 4 mL, 2M THF) was added dropwise to the reaction flask, and stirring was continued for 30 min. Then, the THF solution of the above-mentioned product 3 was slowly added dropwise to the reaction flask, and the reaction was carried out at -78°C for 1 h. The reaction flask was then transferred to room temperature and the reaction was continued for 4 h. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction. The mixed solution was extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated NaCl water, dried over anhydrous Na2SO4, and the oily residue after removing the solvent by rotary evaporation was separated by column chromatography (silica gel column 200-300 mesh, PE:EA=6:1) to obtain colorless oily product 4, 1.03 g, with a yield of 48.5%.
[0038] Step 4: Under argon protection, product 4 (1.03 g, 2.91 mmol) was dissolved in 15 mL of dichloromethane, transferred to an ice bath, stirred for 10 min, and then boron tribromide (BBr3, 7.3 mL, 1 M DCM) was slowly added dropwise and reacted for 5 h. After the reaction, the reaction was quenched with saturated sodium bicarbonate solution until no more bubbles were generated. Then, dilute hydrochloric acid (1 M) was added to adjust the pH to acidic. The mixture was extracted with DCM (3 × 20 mL). The organic phases were combined, washed with saturated NaCl water, dried over anhydrous Na2SO4, and the oily residue after removal of the solvent by rotary evaporation was separated by column chromatography (silica gel column 200-300 mesh, PE:EA = 6:1) to obtain compound 5 (Malabaricone A), 0.35 g, with a yield of 36.7%.
[0039] Malabaricone A structural characterization data: 1 H NMR (400MHz, CDCl3): δ7.30-7.21(m,3H),7.18(d,J=6.6Hz,3H),6.38(d,J=8.2Hz,2H),3.17- 3.07(m,2H),2.65-2.55(m,2H),1.70(q,J=7.3Hz,2H),1.60(d,J=8.7Hz,2H),1.33(s,8H).13C NMR(101MHz, CDCl3): δ207.9,161.2,142.9,135.6,128.3,125.6,110.1,108.4,44.8,36.0,31.5,30.0,28.9,24.4.HRMS(m / z):Calcd for(C 21 H 27 O3)([M+H] + ): 327.1955, found: 327.1947. HPLC-retention time: 15.38min, MeOH / H2O=90:10, 1mL / min, 254nm, purity 99.252%.
[0040] Example 2:
[0041] Using the above method, 9-bromononanoic acid was replaced with 7-bromoheptanoic acid in the first step to synthesize compound 6. Structural characterization data: 1 H NMR (400MHz, CDCl3): δ7.31-7.21(m,3H),7.21-7.14(m,3H),6.38(d,J=8.2Hz,2H), 3.11(t,J=7.4Hz,2H),2.61(t,J=7.7Hz,2H),1.74-1.59(m,4H),1.44-1.35(m,4H). 13 CNMR (100MHz, CDCl3): δ207.8,161.2,142.9,135.6,128.5,128.3,125.6,110.1,108.4,44.7,35.9,31.4,29.2,29.1,24.3.HRMS(m / z): Calcd for (C 19 H 23 O3)([M+H] + ): 299.1636, found: 299.1639. HPLC-retention time: 13.96min, MeOH / H2O=90:10, 1mL / min, 254nm, purity98.074%.
[0042] Example 3:
[0043] Using the above method, 9-bromononanoic acid was replaced with 8-bromooctanoic acid in the first step to synthesize compound 7. Structural characterization data: 1 H NMR (400MHz, CDCl3): δ7.38-7.23(m,3H),7.22-7.17(m,3H),6.40(d,J=8.3Hz,3H),3. 13(t,J=7.7Hz,2H),2.63(t,J=8.1Hz,1H),1.82-1.54(m,2H),1.39(d,J=5.0Hz,10H). 13 C NMR(101MHz, CDCl3): δ207.9,161.2,142.9,135.7,128.3,125.6,108.4,44.8,36.0,31.5,29.3,29.1,24.4.HRMS(m / z):Calcd for(C 20 H 25 O3)([M+H] +): 313.1798, found: 313.1791. HPLC-retention time: 49.97min, MeOH / H2O=90:10, 1mL / min, 254nm, purity90.169%.
[0044] Example 4:
[0045] Using the above method, 9-bromodecanoic acid was replaced with 10-bromodecanoic acid in the first step to synthesize compound 8. Structural characterization data: 1 H NMR (400MHz, CDCl3): δ7.30-7.20(m,3H),7.18(d,J=6.8Hz,3H),6.38(d,J=8.3 Hz,2H),3.21-3.01(m,2H),2.73-2.47(m,2H),1.85-1.44(m,5H),1.31(s,9H). 13 C NMR (100MHz, CDCl3) δ207.9,161.2,143.0,135.6,128.4,128.2,125.6,110.1, 108.4,44.8,36.0,31.5,29.5,29.5,29.4,29.4,29.3,24.4.HRMS(m / z):Calcd for(C 22 H 28 O3)([M+H] + ): 341.2111, found: 341.2113. HPLC-retention time: 27.848min, MeOH / H2O=90:10, 1mL / min, 254nm, purity 96.1135%.
[0046] Example 5:
[0047] Using the above method, 9-bromononanoic acid was replaced with 11-bromonoundecanoic acid in the first step to synthesize compound 9. Structural characterization data: 1 H NMR (400MHz, CDCl3): δ7.32-7.22(m,3H),7.21-7.14(m,3H),6.38(d,J=8.2Hz,2H), 3.11(t,J=7.5Hz,2H),2.67-2.55(m,2H),1.80-1.50(m,5H),1.29(d,J=7.9Hz,12H). 13C NMR (100MHz, CDCl3): δ207.9,161.2,143.0,135.6,128.4,128.2,125.6,108.5,44.8,36.0,31.5,29.5,29.4,24.4.HRMS(m / z): Calcd for (C 23 H 31 O3)([M+H] + ): 355.2268, found: 355.2268. HPLC-retention time: 18.161min, MeOH / H2O=90:10, 1mL / min, 254nm, purity92.946%.
[0048] Example 6:
[0049] Using the above method, phenylmagnesium bromide was replaced with 4-fluorophenylmagnesium bromide in the first step to synthesize compound 10. Structural characterization data: 1 H NMR (400MHz, CDCl3): δ7.23-7.06(m,3H),6.99-6.88(m,2H),6.41(d,J=8.3Hz,2H),3 .14(t,J=7.4Hz,2H),2.56(t,J=7.7Hz,2H),1.75-1.48(m,4H),1.32(d,J=3.9Hz,8H). 13 C NMR (100MHz, CDCl3): δ208.1,162.3,161.7,159.9,138.5,138.5,135.6,129.7,129.6,115 .0,114.8,110.2,108.2,46.1,44.8,35.1,31.6,29.5,29.4,29.1,24.4.HRMS(m / z):Calcd for(C 21 H 25 FO3)([M+H] - ): 345.1861, found: 385.1859. HPLC-retention time: 6.137min, MeOH / H2O=90:10, 1mL / min, 254nm, purity: 99.5054%.
[0050] The compounds prepared in the above examples were further subjected to the following assays:
[0051] Determination of the minimum inhibitory concentration (MIC) of the compounds synthesized in the above examples:
[0052] The methicillin-resistant Staphylococcus aureus (MRSA Mu 50), Staphylococcus epidermidis (ATCC14990), and Enterococcus faecalis strains used in the experiment were from the American Type Culture Collection (ATCC), and the clinical strain of Enterococcus faecium was from the Department of Laboratory, the First Affiliated Hospital of Air Force Medical University.
[0053] The liquid dilution method was used for determination. Specifically, the initial concentration of the four example compounds in the first well was 128 μg / mL, and multiple dilutions were performed horizontally. Subsequently, 100 μL of bacterial liquid (1×10 6 CFU / mL) were added to a microtiter plate and then incubated at 37°C for 24 hours. The final concentration of each compound was 0.25 μg / mL to 128 μg / mL. When the culture medium first became turbid, the drug concentration corresponding to that well was the MIC value of the compound against the bacteria. The results are shown in Table 1. The test results showed that the compounds of Examples 1, 4, 5, and 6 exhibited good antibacterial activity against methicillin-resistant Staphylococcus aureus (Mu50) and Staphylococcus epidermidis (ATCC14990) in vitro. The compounds of Examples 1 and 4 also exhibited good antibacterial activity against Enterococcus faecalis (ATCC29212) and Enterococcus faecium (XJ17030933).
[0054] Table 1
[0055]
[0056] Based on the significant antibacterial effects of the example compounds against MRSA shown in Table 1, the bactericidal characteristics, antibacterial effects, and safety of the compounds of the present invention were further verified using the compound of Example 1 as a representative. Specifically, the effect of the compound of Example 1 on the growth curve of MRSA bacteria was observed using a fully automatic bacterial growth instrument; the effect of the compound on the morphology of MRSA bacteria was observed using an electron microscope; an animal model of MRSA lung infection was constructed to evaluate the in vivo antibacterial effect of the compound; and the effect of the compound on cell viability was observed in four mammalian cell lines.
[0057] Bacterial growth curve determination:
[0058] The effects of the compound of Example 1 and the control antibiotic oxacillin on methicillin-resistant Staphylococcus aureus MRSA (ATCC29213; USA300), Staphylococcus epidermidis (ATCC 14990) and Enterococcus faecalis (ATCC 29212) were determined: the bacterial liquid was diluted to 1×10 6CFU / mL, 150 μL of the compound of Example 1 at different concentrations (0.125 μg / mL, 0.25 μg / mL, 0.5 μg / mL and 1 μg / mL) was added to 150 μL of bacterial suspension, and cultured in a bacterial automatic growth instrument (Helsinki Laboratory Systems, Finland) at 37°C. The density of the bacterial cell suspension was measured at 600 nm. For the control, MH broth medium without the test compound was added. Figure 7 It was shown that the compound of Example 1 had a significant inhibitory effect on the in vitro growth of MRSA in a dose-dependent manner.
[0059] Electron microscopy morphology observation:
[0060] Use 1×10 6 CFU / mL of MRSA (Mu 50) was cultured in MH broth containing the compound of Example 1 (1 μg / mL, 4 μg / mL) and the compound. The bacteria were then collected, washed three times with 0.01 M PBS, added with electron microscopy fixative, and placed in a sample. 3% glutaraldehyde was added for sectioning. The sample was post-fixed with 1% osmium tetroxide (osmium tetroxide) and dehydrated in 50%, 70%, 80%, 90%, and 95% acetone for 15 minutes, respectively. The sample was observed and recorded under a transmission electron microscope (JEM-1230, JOEL, Tokyo, Japan). The results are shown in FIG. Figure 8 As shown in the morphological study of MRSA (USA300) under transmission electron microscopy, the morphology of the MRSA (USA300) strain and the group treated with the compound of Example 1, the original magnifications were 15,000 times (AC) and 30,000 times (DF), respectively. The results showed that the compound of Example 1 was able to rupture the MRSA bacterial cells and cause their death.
[0061] In vivo antibacterial activity assay:
[0062] Mice were anesthetized with isoflurane and placed in an upright position. 8 80 μL of MRSA (USA 300) bacterial solution with a CFU / mL was dripped into the left nose of the mouse, and then the mouse was kept in an upright position for 2 minutes to allow the bacterial solution to be fully absorbed into the lungs to establish an in vivo lung infection model. The animals were divided into a normal control group (Control), a model group (Model), a 25 mg / kg oxacillin treatment group (Oxacillin), and a treatment group with different doses of the compound of Example 1 (1, 5, 10, 25 mg / kg). The drugs were administered by intraperitoneal injection, and the drugs were administered once at 0h, 8h and 16h respectively. The lung tissues of the mice in the above groups were ground, and the bacterial load was counted after plating. The results are as follows: Figure 9As shown, the results indicate that the compound of Example 1 at different doses can significantly reduce the number of bacteria in lung tissue, suggesting that it has a good antibacterial effect in vivo.
[0063] E. Cytotoxicity assay
[0064] The cytotoxicity of the compound of Example 1 on human intestinal epithelial cells (HIEC cells), mouse brain microvascular endothelial cells (Bend.3 cells), mouse cardiomyocytes (HL-1 cells) and human non-small cell lung cancer cells (A549 cells) was detected by CCK-8 assay. 4 Cells / well) were treated with different concentrations of the compound of Example 1 (0, 5, 10, 15, 20, 25 μg / mL); after 24 hours, 10% CCK-8 reagent was added, incubated at 37°C for 1 hour, and then the absorbance was measured at 450 nm. The results are shown in Figure 2. Figure 10 As shown, the effects of different concentrations of the compound of Example 1 on the viability of mammalian cells after 24 hours of treatment (n=5): (A) human intestinal epithelial cells; (B) mouse brain microvascular endothelial cells; (C) mouse cardiomyocytes; (D) human non-small cell lung cancer cells. Figure 10 As shown, the above results indicate that the compound of Example 1 has little effect on the viability of mammalian cells. In particular, compared with the MIC value, the concentration of the compound affecting cell growth differs by 50-100 times, indicating good safety.
[0065] According to the experimental data in the above specific examples, the Malabaricone A compound of the present invention and its analogs have demonstrated significant anti-MRSA activity in vitro and in vivo. Among them, the minimum inhibitory concentration (MIC) of Examples 1, 4, 5, and 6 is much lower than that of clinical first-line antibacterial drugs such as oxacillin, and has good safety. This patent discloses a new method for the total synthesis of such compounds for the first time, laying an important foundation for large-scale preparation. The compound shows promising development potential and is expected to become a new type of antibacterial drug with a new skeleton and can effectively address the problem of bacterial resistance.
Claims
1. Malabaricone A and its analogs, the structures of which are shown in Formula I: R is H or F, n=4, 5, 6, 7, 8.
2. Malabaricone A and its analogs according to claim 1, characterized in that R is F, n=6.
3. Use of Malabaricone A and its analogs or pharmaceutically acceptable salts according to claim 1 or 2 in preparing anti-MRSA drugs.
4. A method for synthesizing Malabaricone A and its analogs, characterized in that: The method comprises: Step 1: Under the protection of inert gas and the presence of a catalyst, bromic acid as a raw material reacts with aryl magnesium bromide to prepare an aryl carboxylic acid; the catalyst is selected from ferric acetylacetonate; the bromic acid is 9-bromononanoic acid, 7-bromoheptanoic acid, 8-bromooctanoic acid, 10-bromodecanoic acid or 11-bromodecaneic acid; Step 2: Under alkaline conditions and in the presence of a condensing agent and a protecting agent, the aryl carboxylic acid obtained in step 1 is reacted to prepare an N,O-dimethyl-protected aryl carboxylic acid; the condensing agent is selected from N,N-carbonyldiimidazole; and the protecting agent is selected from N,O-dimethylhydroxylamine hydrochloride; Step 3: Under the protection of an inert gas and in the presence of an activating reagent, the N,O-dimethyl-protected aryl carboxylic acid obtained in step 2 reacts with 2,6-dimethoxybromobenzene to achieve debromination coupling between the carbonyl carbon atom and the aryl carbon atom; the activating reagent is n-butyl lithium; Step 4: Under inert gas protection and ice bath conditions, the product obtained in step 3 reacts with boron tribromide to remove the methyl group in the methoxy group to obtain Malabaricone A and its analogs.
5. The preparation method according to claim 4, characterized in that The catalyst in step 1 is a catalytic system consisting of ferric acetylacetonate, hexamethylenetetramine and N,N,N,N-tetramethylethylenediamine.
6. The preparation method according to claim 4, characterized in that The arylmagnesium bromide is phenylmagnesium bromide or 4-fluorophenylmagnesium bromide.
7. The preparation method according to claim 4, characterized in that The step 3 comprises: 3.1 Dissolve the product of step 2 in an organic solvent under inert gas protection; 3.2 Under inert gas protection and -80 to -75°C, 2,6-dimethoxybromobenzene is dissolved in an organic solvent and n-butyl lithium is added dropwise; 3.3 Under inert gas protection, add the mixed solution of step 3.1 dropwise to the mixed solution of step 3.2, react at -80 to -75°C, then heat to room temperature and continue the reaction to achieve debromination coupling of the carbonyl carbon atom and the aromatic carbon atom.