Synthesis of 9-phenyl-10-alkoxy evodiamine quinazolinone derivative and anti-cancer application of 9-phenyl-10-alkoxy evodiamine quinazolinone derivative

Abstract

The invention discloses 9-phenyl-10-alkoxy evodiamine quinazolinone with a structural formula as shown in a formula 3, wherein R is selected from alkyl or substituted alkyl. The designed and synthesized 9-phenyl-10-alkoxy evodiamine quinazolinone derivative as shown in 3 is prepared by the following steps: (1) taking 10-hydroxy evodiamine (A) as a raw material, and reacting with an alkylation reagent (RX) in the presence of a proper alkali catalyst under proper conditions to obtain 10-alkoxy evodiamine 1, 2, 3-triazole; (2) reacting the compound 1 with a bromination reagent under proper conditions to obtain 9-bromo-10-alkoxy evodiamine 2; and (3) reacting the compound 2 with an arylboronic acid reagent under proper conditions to obtain the 9-phenyl-10-alkoxy evodiamine quinazolinone derivative 3. The 9-phenyl-10-alkoxy evodiamine quinazolinone derivative synthesized by the invention shows good anti-cancer activity on liver cancer cells and neuroblastoma cells in vitro, and can be used for preparing corresponding anti-cancer drugs.

Description

Technical Field

[0001] The present invention belongs to the field of new drug design and synthesis, and specifically relates to the synthesis of a 9-phenyl-10-alkoxyevodiamine quinazolinone derivative and its anticancer application. Background Art

[0002] Quinazolinones are a class of nitrogen-containing heterocyclic compounds whose core structure consists of a fused benzene ring and a pyrimidinone ring. They possess a wide range of biological activities, including antitumor, antibacterial, and anti-inflammatory effects. Among natural products, quinazolinones are primarily produced by microorganisms such as Streptomyces and Aspergillus, or through plant metabolism. Some natural product structures, including camptothecin and evodiamine, have been shown to possess promising antitumor activity. Aryl conjugation is an important strategy for drug structure modification. By introducing aromatic rings or constructing aromatic-aromatic (C-C or C-X) bonds, the physicochemical properties, bioactivity, and pharmacokinetic properties of drugs can be significantly optimized. For example, aromatic conjugation can increase the rigidity and conjugation of the molecule, enhancing its binding to target proteins. Given the promising biological activity of quinazolinones, structural modification to further enhance their performance is of great research value. However, in the current prior art, CN110272392A discloses “Transition metal-catalyzed C-H coupling for efficient preparation of 2-(4(3H)-quinazolinone) aryl acetate alkyl ester derivatives”, which involves using 5-diazo Michaelis acid as an alkylating agent and a transition metal-catalyzed C-H coupling reaction to prepare 2-(4(3H)-quinazolinone) aryl acetate alkyl ester derivatives. This invention uses 2-phenyl-4(3H)-quinazolinone compounds as substrates and utilizes a transition metal-catalyzed C-H coupling reaction. In 2020, Kim et al. used ruthenium (II)-catalyzed C-H activation to cause a cross-coupling reaction between 2-arylquinazolinone and activated aldehyde to obtain tetracyclic quinazolinone derivatives. This method also provides a pathway based on transition metal-catalyzed C-H activation. Although transition metal catalysis plays an important role in fields such as organic synthesis, it also has some obvious disadvantages, including high cost, difficulty in catalyst recovery and reuse, and limited substrate applicability. Therefore, the development of other methods to introduce aromatic coupling into the structural modification of quinazolinone is expected to obtain new quinazolinone derivatives with better activity and pharmacokinetic properties, opening up new paths for the research and development of anti-tumor drugs and other drugs. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention researches and designs a series of novel 9-phenyl-10-alkoxyevodiamine quinazolinone derivatives. By introducing an alkoxy group at the C-10 position of the 10-hydroxyevodiamine parent structure via an alkylation reaction and a phenyl group at the C-9 position via a Suzuki reaction, a series of novel 9-phenyl-10-alkoxyevodiamine quinazolinone derivatives were synthesized. Activity studies have shown that these novel derivatives have a significant inhibitory effect on liver cancer and neuroblastoma cells.

[0004] One of the purposes of the present invention is to provide 9-phenyl-10-alkoxyevodiamine quinazolinone derivatives, the structural formula of which is as follows:

[0005] As shown in formula 3,

[0006]

[0007] wherein R is selected from alkyl or substituted alkyl.

[0008] Preferably, R is selected from C1-C7 alkyl or substituted alkyl, including methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.

[0009] Another object of the present invention is to provide a method for synthesizing the above-mentioned 9-phenyl-10-alkoxyevodiamine quinazolinone derivative 3, the synthetic route of which is:

[0010]

[0011] The method comprises the following steps: (1) using 10-hydroxyevodiamine (A) as a raw material and reacting it with an alkylating agent RX in the presence of a suitable base catalyst under suitable conditions to obtain 10-alkoxyevodiamine 1; (2) reacting compound 1 with a brominating agent to obtain 9-bromo-10-alkoxyevodiamine 2; and (3) reacting compound 2 with an aryl boronic acid reagent [PhB(OH)2] to obtain a 9-phenyl-10-alkoxyevodiamine quinazolinone derivative 3; wherein R of the alkylating agent RX in step (1) is selected from an alkyl group or a substituted alkyl group, and X is selected from I or Br.

[0012] Preferably, in step (1), the appropriate base catalyst is selected from carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate, preferably cesium carbonate.

[0013] Preferably, in step (2), the brominating agent is selected from liquid bromine (Br2) or N-bromosuccinimide (NBS).

[0014] Preferably, in step (3), the aryl boronic acid reagent is selected from phenylboronic acid; and the base catalyst is selected from carbonates, such as sodium carbonate, potassium carbonate, lithium carbonate or cesium carbonate, preferably cesium carbonate.

[0015] Preferably, the appropriate conditions in step (1) are to use N,N-dimethylformamide (DMF) as the reaction solvent, the reaction time is 1 to 2 hours, and the reaction temperature is 0°C to room temperature; the appropriate conditions in step (2) are to use chloroform or dichloromethane as the reaction solvent, the reaction time is 0.5 to 2 hours, preferably 1 hour, and the reaction temperature is 0°C to room temperature; the appropriate conditions in step (3) are to use 1,4-dioxane as the reaction solvent, the reaction time is 12 to 24 hours, preferably 24 hours; and the reaction temperature is 50°C to 80°C, preferably 60°C to 70°C.

[0016] The present invention also provides the use of 9-phenyl-10-alkoxyevodiamine quinazolinone derivatives 3 in the preparation of anticancer drugs.

[0017] Preferably, the above 9-phenyl-10-alkoxyevodiamine quinazolinone derivative 3 is used in the preparation of two anticancer drugs for liver cancer and neuroblastoma.

[0018] The present invention has the following beneficial effects: the raw materials, reagents, and solvents used in the synthesis method are inexpensive and readily available; the synthesis method is performed under mild conditions and is easy to operate. The 9-phenyl-10-alkoxyevodiamine quinazolinone derivative 3 synthesized by the present invention has a good inhibitory effect on HepG2 liver cancer and SK-N-SH neuroblastoma tumor cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 is the 1H NMR spectrum of compound 1a; Figure 2 is the 13C NMR spectrum of compound 1a;

[0020] Figure 3 is the 1H NMR spectrum of compound 1b; Figure 4 is the 13C NMR spectrum of compound 1b;

[0021] Figure 5 is the 1H NMR spectrum of compound 1c; Figure 6 is the 13C NMR spectrum of compound 1c;

[0022] Figure 7 is the 1H NMR spectrum of compound 1d; Figure 8 is the 13C NMR spectrum of compound 1d;

[0023] Figure 9 is the 1H NMR spectrum of compound 1e; Figure 10 is the 13C NMR spectrum of compound 1e;

[0024] Figure 11is the 1H NMR spectrum of compound 1f; Figure 12 is the 13C NMR spectrum of compound 1f;

[0025] Figure 13 is the 1H NMR spectrum of compound 2a; Figure 14 is the 13C NMR spectrum of compound 2a;

[0026] Figure 15 is the 1H NMR spectrum of compound 2b; Figure 16 is the 13C NMR spectrum of compound 2b;

[0027] Figure 17 is the 1H NMR spectrum of compound 2b1; Figure 18 is the 13C NMR spectrum of compound 2b1;

[0028] Figure 19 is the 1H NMR spectrum of compound 2b2; Figure 20 is the 13C NMR spectrum of compound 2b2;

[0029] Figure 21 is the 1H NMR spectrum of compound 2b3; Figure 22 is the 13C NMR spectrum of compound 2b3;

[0030] Figure 23 is the 1H NMR spectrum of compound 2c; Figure 24 is the 13H NMR spectrum of compound 2c;

[0031] Figure 25 is the 1C NMR spectrum of compound 2d; Figure 26 is the 13H NMR spectrum of compound 2d;

[0032] Figure 27 is the 1C NMR spectrum of compound 2e; Figure 28 is the 13H NMR spectrum of compound 2e;

[0033] Figure 29 is the 1C NMR spectrum of compound 2f; Figure 30 is the 13H NMR spectrum of compound 2f;

[0034] Figure 31 is the 1C NMR spectrum of compound 2g; Figure 32 is the 13H NMR spectrum of compound 2g;

[0035] Figure 33is the 1C NMR spectrum of compound 2h; Figure 34 is the 13H NMR spectrum of compound 2h;

[0036] Figure 35 is the 1H NMR spectrum of compound 3a; Figure 36 is the 13C NMR spectrum of compound 3a;

[0037] Figure 37 is the 1H NMR spectrum of compound 3b; Figure 38 is the 13C NMR spectrum of compound 3b;

[0038] Figure 39 is the 1H NMR spectrum of compound 3c; Figure 40 is the 13H NMR spectrum of compound 3c;

[0039] Figure 41 is the 1C NMR spectrum of compound 3d; Figure 42 is the 13H NMR spectrum of compound 3d;

[0040] Figure 43 is the 1C NMR spectrum of compound 3e; Figure 44 is the 13H NMR spectrum of compound 3e;

[0041] Figure 45 is the 1C NMR spectrum of compound 3f; Figure 46 is the 13H NMR spectrum of compound 3f;

[0042] Figure 47 is the 1C NMR spectrum of compound 3g; Figure 48 is the 13H NMR spectrum of compound 3g;

[0043] Figure 49 is the 1C NMR spectrum of compound 3h; Figure 50 This is the 13H NMR spectrum of compound 3h. DETAILED DESCRIPTION

[0044] The following is further described in detail through specific implementation methods:

[0045] In the following examples, unless otherwise stated, the experimental methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown can be obtained through commercial purchase.

[0046] Example 1 Preparation of Compounds 1b-1h

[0047] (1) Preparation of 10-alkoxyevodiamine quinazolinone compounds (Ib-1h)

[0048]

[0049] Literature has reported that 10-OH evodiamine (compound 1a) reacts with an alkylating agent (RX). In the reported reaction conditions, K2CO3 is used as a base, EtOH is used as a solvent, and reflux reaction is performed for 6 hours to synthesize 10-OH evodiamine with a high yield to connect several 10-OR evodiamine intermediates such as ethyl, propyl, benzyl and propynyl. However, under this condition, we did not achieve the desired effect when reacting with the corresponding alkylating agent. For example, when connecting to an ethyl group, the yield may not be high because the boiling point of bromoethane is lower than the reflux temperature, and the longer reaction time also makes it possible that some irreversible combinations occur between 10-OH evodiamine and the base, thereby causing raw material recovery to be less. Therefore, the inventors have carried out process optimization to the reaction conditions on this basis, and utilized the optimized reaction conditions to synthesize and prepare other intermediates 1b-1h with a series of alkylating agents.

[0050] Taking compound 1b as an example, the optimized synthesis process and conditions are as follows:

[0051]

[0052] 10-OH evodiamine (compound 1a, 50 mg, 0.16 mmol) and Cs2CO3 (51 mg, 0.16 mmol) were weighed into a dry two-necked flask and filled with N2. 1 mL of anhydrous DMF was added for dissolution. Methyl iodide (12 μL, 0.19 mmol) was then added and allowed to react at room temperature for 2 h. The reaction was monitored by TLC and terminated when the starting material was completely eliminated. The reaction was quenched by the addition of 10 mL of water and extracted with ethyl acetate (20 mL x 3). The pH was adjusted to a weak acidic state with 2% HCl. The combined extracts were dried over anhydrous Na2SO4 and the solvent was removed by distillation under reduced pressure to obtain a crude yellow oil. Purification by column chromatography (PE:EA = 4:1) afforded pure product 1b in a 78% yield.

[0053] The optimal reaction conditions were determined to be: DMF as the reaction solvent, Cs2CO3 as the base catalyst, and 2 hours at room temperature. To conduct subsequent activity experiments and better explore the possible structure-activity relationship, we synthesized a series of eight 10-alkoxyevodiamine derivatives.

[0054]

[0055] Compound 1b (white solid, 42 mg, yield 78%), TLC thin layer chromatography R f=0.27 (eluent: petroleum ether PE:ethyl acetate EA = 3:1). 1 H NMR (400MHz, DMSO-d6), δ: 10.87 (s, 1H), 7.77 (dd, J = 7.7, 1.7Hz, 1H), 7.44 (tt, J = 8.6, 1.6Hz,1H),7.23(d,J=8.7Hz,1H),7.01(d,J=8.2Hz,1H),6.97–6.88(m,2H),6.78–6.6 7(m,1H),6.08(s,1H),4.60(dd,J=12.9,5.3Hz,1H),3.78–3.70(m,3H),3.16(td,J=12 .1,4.5Hz,1H),2.92–2.86(m,3H),2.83(d,J=5.9Hz,1H),2.73(dd,J=15.4,4.4Hz,1H). 13 C NMR (101MHz, DMSO-d6), δ: 164.71, 153.79, 149.12, 133.92, 131.92, 131.72, 128.42, 126.72, 120.58,119.51,117.68,112.79,112.41,111.73,100.44,70.30,55.76,41.42,36.82,20.00.

[0056]

[0057] Referring to the above synthesis method and process conditions, compound 1c (white solid 45 mg, yield 52%) was obtained. TLC thin layer chromatography R f =0.27 (eluent: petroleum ether PE:ethyl acetate EA = 3:1). 1 H NMR (400MHz, DMSO-d6), δ: 8.30 (s, 1H), 8.10 (dd, J=7.9, 1.6Hz, 1H), 7.47 (td, J=7.6, 1.6Hz, 1H),7.29(d,J=8.8Hz,1H),7.19(t,J=7.5Hz,1H),7.12(d,J=8.0Hz,1H),7.00(d,J=2.4Hz,1H ),6.90(dd,J=8.8,2.4Hz,1H),5.88(s,1H),4.86(dt,J=12.9,3.7Hz,1H),4.08(q,J=7.0Hz,2 H),3.31–3.21(m,1H),2.90(ddd,J=9.1,4.7,2.7Hz,2H),2.49(s,3H),1.44(t,J=7.0Hz,3H). 13C NMR (101MHz, CDCl3), δ: 164.77, 153.60, 150.62, 133.26, 132.87, 131.73, 128.91, 126.60, 123. 82,122.43,122.12,113.82,113.31,112.25,101.58,68.95,64.20,64.20,36.99,20.16,14.94.

[0058]

[0059] Referring to the above synthesis method and process conditions of compound 1b, compound 1d (white solid 45 mg, yield 66%) was obtained. TLC thin layer chromatography R f =0.14 (eluent: petroleum ether PE:ethyl acetate EA = 3:1). 1 H NMR (400MHz, DMSO-d6), δ: 10.83 (s, 1H), 7.74 (dd, J = 7.8, 1.6 Hz, 1H), 7.43 (ddd, J = 8.5, 7.3, 1. 7Hz,1H),7.21(d,J=8.8Hz,1H),6.98(d,J=8.2Hz,1H),6.94–6.87(m,2H),6.71(dd,J=8.8,2.4 Hz,1H),6.05(s,1H),4.62–4.54(m,1H),3.85(t,J=6.6Hz,2H),3.18–3.12(m,1H),2.87(s,3H) ,2.85–2.79(m,1H),2.69(dd,J=15.4,4.5Hz,1H),1.68(q,J=7.0Hz,2H),0.93(t,J=7.4Hz,3H). 13 C NMR (101MHz, DMSO-d6), δ: 164.85, 153.09, 148.96, 134.05, 131.85, 131.79, 128.38, 126.74, 120.45 ,119.14,117.41,112.87,112.78,111.68,101.42,70.41,69.86,41.56,36.81,22.67,19.91,10.96.

[0060]

[0061] Referring to the above synthesis method and process conditions of compound 1b, compound 1e (white solid 125 mg, yield 53%) was obtained. TLC thin layer chromatography R f =0.39 (eluent: petroleum ether PE:ethyl acetate EA = 3:1).1 H NMR (400MHz, DMSO-d6), δ: 10.85(s,1H),7.77(dd,J=7.8,1.7Hz,1H),7.49–7.40(m,1H),7.21(d,J=8 .7Hz,1H),7.00(d,J=8.2Hz,1H),6.97–6.88(m,2H),6.72(dd,J=8.8,2.4Hz,1H),6.07(s,1H),4.60(d d,J=13.0,5.2Hz,1H),3.91(t,J=6.5Hz,2H),3.16(td,J=12.0,4.5Hz,1H),2.86(s,3H),2.82(d,J=5 .9Hz,1H),2.71(dd,J=15.7,4.6Hz,1H),1.71–1.62(m,2H),1.47–1.36(m,2H),0.91(t,J=7.3Hz,3H). 13 C NMR (101MHz, DMSO-d6), δ: 164.69, 153.13, 149.10, 133.90, 131.90, 131.70, 128.42, 126.74, 120.56, 11 9.50,117.66,112.85,112.73,111.68,101.41,70.30,67.96,41.42,36.82,31.46,19.98,19.30,14.22.

[0062]

[0063] Referring to the above synthesis method and process conditions of compound 1b, compound 1f (white solid 100 mg, yield 53%) was obtained. TLC thin layer chromatography R f =0.28 (eluent: petroleum ether PE:ethyl acetate EA = 3:1). 1H NMR (400MHz, DMSO-d6), δ: 10.85 (s, 1H), 7.77 (d, J = 7.8Hz, 1H), 7.44 (t, J = 7.7Hz, 1H), 7.21 (d, J = 8. 8Hz,1H),7.00(d,J=8.3Hz,1H),6.93(q,J=5.9Hz,2H),6.77–6.67(m,1H),6.07(s,1H),4.60(dd,J=1 2.9,5.3Hz,1H),3.91(q,J=7.8Hz,2H),3.15(dt,J=12.4,6.0Hz,1H),2.86(s,3H),2.82(d,J=6.0Hz ,1H),2.76–2.68(m,1H),1.68(p,J=6.4Hz,2H),1.36(tt,J=14.5,5.4Hz,4H),0.87(t,J=7.0Hz,3H). 13 C NMR (101MHz, DMSO-d6), δ: 164.69, 153.14, 149.11, 133.89, 131.92, 131.69, 128.42, 126.75, 120.56, 119.5 2,117.66,112.85,112.73,111.68,101.42,70.30,68.27,41.42,36.82,29.08,28.29,22.40,19.98,14.40.

[0064]

[0065] Referring to the above synthesis method and process conditions of compound 1b, compound 1g (white solid 110 mg, yield 52%) was obtained. TLC thin layer chromatography R f =0.30 (eluent: petroleum ether PE:ethyl acetate EA=3:1).

[0066]

[0067] Referring to the above synthesis method and process conditions of compound 1b, compound 1h was obtained (white solid 110 mg, yield 55%), TLC thin layer chromatography Rf = 0.30 (eluent: petroleum ether PE: ethyl acetate EA = 3:1).

[0068] Example 2 Preparation of Compounds 2a-2h

[0069] (1) Preparation of 9-bromo-10-alkoxyevodiamine quinazolinone compounds (2a-2h)

[0070]

[0071] Taking the synthesis of intermediate 2b as an example, the synthesis method and process conditions of this key step were explored. It is intended to introduce an aromatic group into the 9-position of evodiamine through a Suzuki coupling reaction, so it is necessary to first synthesize a 9-halogenated intermediate. For this reason, the structure of the 9-brominated product of evodiamine is relatively stable, and the activity is also high when the next Suzuki coupling reaction is carried out. However, there are many sites in the structure of 10-OR evodiamine that may undergo bromination reactions, and the presence of the 10-alkoxy group of evodiamine will also lead to increased steric hindrance at the 9-position, making it theoretically very difficult to carry out a highly selective bromination reaction at the 9-position.

[0072]

[0073] During the experimental exploration, we strictly controlled the reaction equivalent of the bromination reagent, the addition method, and the reaction temperature and time, as shown in Table 1. We used 10-OCH3 evodiamine (1b) as the raw material and tried to use different bromination reagents to brominate the 9-position to synthesize compound 2b.

[0074] Table 1. Optimization of reaction conditions for intermediate 2b

[0075]

[0076]

[0077] We tried various bromination reagents in the hope of brominating the 9-position of evodiamine. The results in Table 2 show that: (1) As can be seen from conditions 1, 2, and 3, HBr as the bromination reagent did not react in either acidic or aqueous solutions, and NaBr also did not react in 30% H2O2 solution. Therefore, a stronger bromination reagent was required for the reaction. (2) When dichloromethane (DCM) was used as the solvent and NBS (1 equiv.) was used, the reaction occurred at the 3-position of the indole. (3) When Br2 (1 equiv.) was used as the bromination reagent, the reaction occurred at the 9-position of evodiamine. No other positions were substituted, so Br2 could be used as the bromination reagent. (4) When Br2 (2 equiv.) was used, a disubstituted compound was generated, and the reaction occurred at the 3 and 9 positions of the indole ring. When Br2 (4 equiv.) reacts, a trisubstituted compound is generated, and bromine atoms are introduced into the 2, 3, and 9 positions of the indole ring. Therefore, the amount of Br2 must be strictly controlled during the reaction to avoid the formation of by-products. (5) When we replaced DCM with other solvents, such as tetrahydrofuran (THF) or chloroform (CDCl3), the reaction did not occur or was incomplete with residual raw materials. Therefore, Br2 (1 equiv.) was used as the bromination reagent, DCM was used as the solvent, and the reaction temperature was 0℃-rt for 1 hour to synthesize other intermediates. We further confirmed the structure of compound 2b1 by X-ray single crystal diffraction (CCDCnumber: 2224753).

[0078] Taking compound 2b as an example, the synthesis method and process conditions are as follows: 10-OCH3 evodiamine (50 mg, 0.15 mmol) was weighed into a dry two-necked flask, filled with N2 protection, and 2 mL of anhydrous CH2Cl2 was added to dissolve it. Br2 (8 μL, 0.15 mmol) was then dissolved in 1 mL of CH2Cl2. The Br2 / CH2Cl2 solution was slowly added at 0°C. After the addition was complete, the reaction was continued at 0°C-rt for 1 h. The reaction was monitored by TLC. When the starting material was completely eliminated, the reaction was stopped and quenched by adding 10 mL of saturated NaHCO3 aqueous solution. The reaction was extracted with CH2Cl2 (20 mL × 3). The CH2Cl2 extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain a crude yellow solid. The crude product was purified by column chromatography (CH2Cl2:MeOH = 200:1) to obtain pure yellow solid 2b (56 mg, 90% yield). Using eight 10-OR evodiamine intermediates (1a-1h) as reaction raw materials and identifying Br2 as the optimal bromination reagent, we synthesized eight 9-Br evodiamine derivatives (2a-2h) in moderate to high yields. The results are shown in Table 2.

[0079] Table 2. Synthesis conditions of 9-Br-evodiamine intermediates 2a-2h

[0080]

[0081]

[0082] Compound 2a (light yellow solid, yield 85%) was obtained, and TLC thin layer chromatography R f =0.21 (eluent: petroleum ether PE:ethyl acetate EA = 2:1). 1 H NMR (400MHz, DMSO-d6), δ: 10.99(d,J=2.8Hz,1H),9.36(d,J=6.7Hz,1H),7.75(td,J=8.4,7.8,2.1Hz,1H),7.49–7.33(m,1H),7.14(d,J=8.6H z,1H),7.01–6.86(m,2H),6.77(dd,J=8.6,2.0Hz,1H),6.07(s,1H),4.61–4.49(m,1H),3.15(tt,J=20.3,8.1Hz,3H),2.93(d,J=22.6Hz,3H). 13 C NMR (100MHz, DMSO-d6), δ: 164.72, 148.78, 147.69, 134.04, 133.16, 131.79, 128.34, 125. 77,120.39,118.97,117.37,112.80,111.97,111.53,98.92,70.37,41.57,37.15,21.85.

[0083]

[0084] Compound 2b (light yellow solid, yield 90%) was obtained, and TLC thin layer chromatography R f =0.23 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1 H NMR (400MHz, DMSO-d6), δ: 11.15(s,1H),7.74(dd,J=7.8,1.7Hz,1H),7.47–7.41(m,1H),7.29(dd,J=8.8,1.5Hz,1H),7.00( d,J=8.2Hz,1H),6.97–6.89(m,2H),6.11(s,1H),4.62–4.53(m,1H),3.77(s,3H),3.24–3.04(m,3H),2.90(d,J=1.8Hz,3H). 13C NMR (100MHz, DMSO-d6), δ: 164.69, 149.71, 148.82, 134.12 (d, J = 10.1Hz), 133.05, 128.36, 125.9 5,120.53,119.07,117.56,112.00,111.70,110.05,101.45,70.27,57.83,41.49,37.23,21.83.

[0085]

[0086] Compound 2b1 (yellow solid, yield 86%) was obtained, and TLC thin layer chromatography R f =0.40 (eluent: petroleum ether PE:ethyl acetate EA=3:1). 1 H NMR (400MHz, CDCl3), δ: 7.81 (dd, J=8.1, 1.7Hz, 1H), 7.44–7.37 (m, 2H), 7.02 (d, J= 2.5Hz,1H),6.83(dd,J=8.6,2.5Hz,1H),6.75(dd,J=7.9,6.3Hz,2H),6.13(s,1H), 4.79(ddd,J=13.8,4.6,1.7Hz,1H),3.81(s,3H),3.30(ddd,J=14.0,12.0,2.3Hz,1 H), 3.18 (s, 3H), 2.64 (dt, J = 15.1, 2.1Hz, 1H), 1.98 (ddd, J = 15.1, 12.0, 4.5Hz, 1H). 13 C NMR (100MHz, CDCl3), δ: 171.07,162.93,159.26,147.40,145.28,141.61,134.64,134.54,128.81,128.72,122.80,122.69,117.77 ,117.73,117.71,114.69,113.73,111.40,111.36,109.38,109.33,73.72,73.58,62.64,55.89,55.76,40.63,40.53,36.22,36.20.

[0087]

[0088] Compound 2b2 (yellow solid, yield 62%) was obtained, and TLC thin layer chromatography R f =0.42 (eluent: petroleum ether PE:ethyl acetate EA=3:1). 1H NMR (400MHz, CDCl3), δ: 8.47 (s, 1H), 8.09 (d, J = 7.8Hz, 1H), 7.48 (t, J = 7.7Hz, 1H), 7.19 (t, J = 7.6Hz, 1H), 7.14 (d, J = 8.1Hz, 1H), 7.09 (s, 1H), 5.85 (s, 1H),4.82(dd,J=12.7,4.8Hz,1H),3.91(s,3H),3.54(d,J=16.2Hz,1H),3.2 1(td,J=12.2,3.8Hz,1H),3.09(td,J=13.5,11.2,4.9Hz,1H),2.48(s,3H). 13 C NMR (100MHz, CDCl3), δ: 164.59,150.70,150.45,133.28,131.76,131.37,129.00,126.57,1 24.35,123.58,122.52,115.52,112.90,103.50,102.64,68.65,58.17,39.42,37.56,22.02.

[0089]

[0090] Compound 2b3 (yellow solid, yield 80%) was obtained, and TLC thin layer chromatography R f =0.45 (eluent: petroleum ether PE:ethyl acetate EA=4:1). 1 H NMR (400MHz, CDCl3), δ: 8.32 (s, 1H), 8.21 (s, 1H), 7.58 (d, J = 8.6Hz, 1H), 7.25 (s, 2H), 7.10 (s, 1H), 7.04 (d, J = 8.3Hz, 1H), 5.84 (s,1H),4.84–4.75(m,1H),3.92(s,3H),3.56(d,J=15.6Hz,1H),3.22(dd,J=14.4,10.8Hz,1H),3.17–3.08(m,1H),2.47(s,3H). 13 C NMR (100MHz, CDCl3), δ: 162.29,149.76,148.23,135.11,130.65,129.79,125.48,124.1 0,123.25,116.34,114.63,112.00,102.46,101.65,67.56,57.13,38.57,36.47,20.90.

[0091]

[0092] Compound 2c (light yellow solid, yield 86%) was obtained, and TLC thin layer chromatography R f =0.23 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1 H NMR (400MHz, DMSO-d6), δ: 11.15 (s, 1H), 7.75 (d, J = 7.7Hz, 1H), 7.44 (t, J = 7.8Hz, 1H), 7.27 (d, J = 8.7Hz, 1H), 7.00 (d, J = 8.3Hz, 1H), 6.93 (d, J=8.9Hz,2H),6.10(s,1H),4.56(d,J=11.1Hz,1H),4.00(q,J=7.2Hz,2H),3.16(dt,J=28.4,14.5Hz,3H),2.90(s,3H),1.29(t,J=7.0Hz,3H). 13 C NMR (100MHz, DMSO-d6), δ: 164.68,148.97,148.86,134.04,133.95,133.17,128.37,125.89,120 .55,119.15,117.60,112.09,112.02,111.86,102.77,70.28,66.57,41.47,37.23,21.87,15.47.

[0093]

[0094] Compound 2d (light yellow solid, yield 87%) was obtained, and TLC thin layer chromatography R f =0.24 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1 H NMR (400MHz, DMSO-d6), δ: 11.15 (s, 1H), 7.75 (d, J = 7.7Hz, 1H), 7.49–7.40 (m, 1H), 7.26 (d, J = 8.7Hz, 1H), 7.00 (d, J = 8.2Hz, 1H), 6.92 (d, J = 8.2Hz, 2H),6.10(s,1H),4.60–4.52(m,1H),3.91(t,J=6.5Hz,2H),3.16(dt,J=2 8.3,14.1Hz,3H),2.89(s,3H),1.76–1.63(m,2H),0.98(t,J=7.4Hz,3H). 13C NMR (100MHz, DMSO-d6), δ: 164.67, 149.09, 148.88, 134.02, 133.92, 133.10, 128.37, 125.89, 120.57 ,119.19,117.65,112.01,111.86,111.84,102.59,72.32,70.26,41.44,37.22,22.86,21.87,11.02.

[0095]

[0096] Compound 2e (light yellow solid, yield 84%) was obtained, and TLC thin layer chromatography R f =0.25 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1 H NMR (400MHz, DMSO-d6), δ: 11.15(s,1H),7.78–7.71(m,1H),7.49–7.40(m,1H), 7.26(d,J=8.7Hz,1H),7.00(d,J=8.3Hz,1H),6.96–6.87(m,2H),6.10(s,1H),4. 62–4.52(m,1H),3.95(t,J=6.5Hz,2H),3.24–3.14(m,2H),3.13–3.04(m,1H),2 .89(s,3H),1.66(t,J=7.2Hz,2H),1.45(q,J=7.5Hz,2H),0.90(t,J=7.4Hz,3H). 13 C NMR (100MHz, DMSO-d6), δ: 169.44, 153.85, 153.59, 138.81, 138.70, 137.82, 130.62, 125.30, 12 3.88,122.36,116.76,116.56,107.28,75.20,75.01,46.22,41.97,36.30,26.60,24.00,18.93.

[0097]

[0098] Compound 2f (light yellow solid, yield 81%) was obtained, and TLC thin layer chromatography R f =0.25 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1H NMR (400MHz, DMSO-d6), δ: 11.15 (s, 1H), 7.75 (d, J = 7.7Hz, 1H), 7.44 (t, J = 7.7Hz, 1H), 7.26(d,J=8.7Hz,1H),7.00(d,J=8.2Hz,1H),6.92(d,J=8.3Hz,2H),6.10(s,1H),4.61– 4.51(m,1H),3.94(t,J=6.5Hz,2H),3.16(ddd,J=27.8,15.8,12.3Hz,3H),2.89(s,3H), 1.68(p,J=6.8Hz,2H),1.46–1.36(m,2H),1.31(h,J=7.1Hz,2H),0.86(t,J=7.2Hz,3H). 13 C NMR (100MHz, DMSO-d6), δ: 164.67, 149.12, 148.87, 134.03, 133.93, 133.11, 128.37, 125.88, 120.56, 119.1 7,117.62,112.02,111.89,111.84,102.60,70.80,70.27,41.45,37.22,29.16,28.19,22.32,21.87,14.42.

[0099]

[0100] Compound 2g (light yellow solid, yield 80%) was obtained, and TLC thin layer chromatography R f =0.26 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1 H NMR (400MHz, DMSO-d6), δ: 11.17 (s, 1H), 7.74 (dd, J = 7.8, 1.6Hz, 1H), 7.48–7.40 (m, 1H), 7 .26(d,J=8.8Hz,1H),6.99(d,J=8.2Hz,1H),6.91(t,J=8.7Hz,2H),6.10(s,1H),4.56(dd,J =14.0,6.7Hz,1H),3.99–3.90(m,2H),3.23–3.15(m,2H),3.14–3.07(m,1H),2.90(s,3H),1 .70–1.64(m,2H),1.44(d,J=7.5Hz,2H),1.27(h,J=4.0Hz,4H),0.84(q,J=5.0,3.3Hz,3H). 13C NMR (100MHz, DMSO-d6), δ: 164.70,149.12,148.83,134.05,133.94,133.09,128.36,125.89,120.52,119.09,1 17.55,112.01,111.86,111.83,102.58,70.79,70.30,41.48,37.21,31.40,29.41,25.64,22.54,21.86,14.36.

[0101]

[0102] Compound 2h (light yellow solid, yield 83%) was obtained, and TLC thin layer chromatography R f =0.27 (eluent: petroleum ether PE:ethyl acetate EA=2:1). 1 H NMR (400MHz, DMSO-d6), δ: 11.13 (s, 1H), 7.74 (dd, J = 7.8, 1.7 Hz, 1H), 7.43 (ddd, J = 8.6, 7.3, 1 .7Hz,1H),7.26(d,J=8.7Hz,1H),6.99(d,J=8.2Hz,1H),6.91(d,J=8.3Hz,2H),6.09(s,1H),4. 56(dd,J=14.2,6.5Hz,1H),3.98–3.88(m,2H),3.23–3.13(m,2H),3.13–3.04(m,1H),2.90(s,3 H),1.66(p,J=6.7Hz,2H),1.41(dd,J=10.4,5.0Hz,2H),1.32–1.19(m,6H),0.86–0.78(m,3H). 13 C NMR (100MHz, DMSO-d6), δ: 164.73, 149.10, 148.78, 134.09, 133.98, 133.06, 128.35, 125.88, 120.49, 118.99, 117. 48,112.02,111.85,111.81,102.55,70.77,70.33,41.52,37.22,31.71,29.43,28.85,25.93,22.49,21.85,14.40.

[0103] Example 3 Preparation of Compounds 3a-3h

[0104] (1) Preparation of 9-aryl-10-alkoxyevodiamine quinazolinone compounds (3a-3h)

[0105] Synthesis exploration experiment: After obtaining the 9-Br evodiamine intermediate, taking compound 2b as an example, we introduced the aromatic ring into the 9-position of evodiamine through Suzuki coupling reaction to obtain compound 3b.

[0106]

[0107] Synthesis of 9-aryl-10-alkoxyevodiamine quinazolinone compound 3b

[0108] Table 3 shows the optimization process for the reaction conditions. 1,4-dioxane is a classic solvent for the Suzuki coupling reaction and has good solubility for evodiamine, so 1,4-dioxane was initially selected as the solvent for the reaction. Phenylboronic acid should be used in excess to ensure sufficient reaction progress. As shown in the table, Na2CO3 (1 equiv.) may react with the starting material to form a salt due to the presence of an active hydrogen on the indole nitrogen atom of evodiamine, resulting in no product formation. A strong base can increase reaction rate and yield. Cs2CO3 is more alkaline than K2CO3 and Na2CO3, and its effect on the reaction is superior to the other two bases. When other solvents were used, the starting material was destroyed by the strong alkalinity of Cs2CO3, possibly because DMF and DMSO are both polar solvents and the reaction temperature is high. Using THF as the solvent resulted in insufficient reaction, resulting in residual starting material. Pd(PPh3)4 is the most commonly used catalyst in the Suzuki coupling reaction, and this reaction does not require any ligand. The optimal reaction conditions were 20% Pd(PPh₃)₄ catalysis, 1,4-dioxane as solvent, phenylboronic acid (1.5 equiv.) and Cs₂CO₃ (2 equiv.) at 70°C for 24 h, affording the desired product in high yield. Proton and carbon spectroscopy confirmed the introduction of an aromatic ring into the evodiamine structure, but it was unclear whether the ring was introduced at the 9-position. Single crystal diffraction analysis of compound 3b confirmed the presence of the aromatic ring at the 9-position and further confirmed the presence of Br₂ bromide at the 9-position (single crystal diffraction data are provided in the Appendix, CCDC number: 2370189).

[0109] Table 3. Optimization of conditions for 9-aryl-10-alkoxyevodiamine quinazolinone compound 3b

[0110]

[0111] Taking compound 3b as an example, the synthesis method is as follows: Compound 2b (50 mg, 0.13 mmol), PhB(OH)2 (23 mg, 0.19 mmol), Cs2CO3 (80 mg, 0.25 mmol), and Pd(PPh3)4 (10 mg) were weighed into a dry two-necked flask, purged with N2, and dissolved in 3 mL of anhydrous 1,4-dioxane. The mixture was reacted at 70°C for 24 h. The reaction was monitored by TLC. When the starting material was no longer present, the reaction was terminated. The mixture was quenched by the addition of 10 mL of water and extracted with CH2Cl2 (20 mL x 3). The CH2Cl2 extracts were combined, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure to obtain a crude black oily solid. This was then purified by column chromatography (PE:EA = 4:1) to obtain pure 3b (44 mg, 84%) as a yellow solid. After determining the optimal experimental conditions, we synthesized eight 9-aryl evodiamine derivatives (3a-3h) in moderate to high yields. The results are shown in Table 4.

[0112]

[0113] Table 4. Synthesis conditions of 10-alkoxy-9-aryl-evodiamine derivatives 3a-3h

[0114]

[0115]

[0116] Compound 3a (light yellow solid, yield 86%) was obtained, and TLC thin layer chromatography R f =0.20 (eluent: petroleum ether CH2Cl2). Mp 191.4-192.7℃. 1 H NMR (400MHz, CDCl3), δ: 8.48 (s, 1H), 8.06 (s, 1H), 7.48 (s, 6H), 7.27 (s, 1H), 7.11 (d, J = 22.7Hz, 2H),6.94(s,1H),5.79(s,1H),5.00(s,1H),4.53(s,1H),2.98(s,1H),2.53(s,3H),2.40(s,1H). 13C NMR (100 MHz, CDCl3), δ: 164.62, 150.41, 146.55, 134.58, 133.10, 131.63, 131.16, 130.32, 129.60, 129.06, 128.85, 128.81, 128.30, 125.04, 123.71, 123.19, 121.84, 118.48, 112.98, 112.33, 111.61, 68.86, 39.63, 37.21, 21.62. HRMS-ESI (m / z): calcd. 25 H 21 N3O2Na[M+Na] + :418.1526, measured value 418.1521.

[0117]

[0118] Compound 3b (light yellow solid, yield 84%) was obtained, and TLC thin layer chromatography R f =0.28 (eluent: petroleum ether CH2Cl2). Mp 148.3-149.7℃. 1 H NMR (400MHz, CDCl3), δ: 8.85(s,1H),8.07(d,J=6.3Hz,1H),7.47–7.32(m,7H),7.06(ddd,J=22.6,14.8,8.2Hz,3H),5.78(s,1H),4.6 4–4.45(m,1H),3.74(s,3H),2.96(td,J=12.3,4.1Hz,1H),2.54(s,3H),2.42(ddd,J=16.7,10.8,4.7Hz,1H),1.92(d,J=14.6Hz,1H). 13 C NMR (100 MHz, CDCl3), δ: 164.64, 150.79, 150.58, 136.56, 133.11, 132.49, 130.76, 130.53, 129.95, 128.91, 127.81, 127.59, 127.17, 125.97, 123.86, 123.42, 123.25, 122.03, 113.51, 110.82, 110.50, 68.83, 58.01, 39.64, 37.17, 21.94. HRMS-ESI (m / z): calcd. 26 H 23 N3O2Na[M+Na] + :432.1683, measured value 432.1682.

[0119]

[0120] Compound 3c (light yellow solid, yield 86%) was obtained, and TLC thin layer chromatography R f =0.23 (eluent: petroleum ether CH2Cl2). Mp 191.0-193.8℃. 1 H NMR (400MHz, CDCl3), δ: 8.60 (s, 1H), 8.06 (d, J = 7.8Hz, 1H), 7.49–7.34 (m, 6H), 7.31 ( d,J=8.7Hz,1H),7.13(t,J=7.5Hz,1H),7.07(d,J=8.1Hz,1H),7.02(d,J=8.8Hz,1H), 5.79(s,1H),4.58–4.48(m,1H),4.00–3.86(m,2H),2.96(td,J=12.3,4.1Hz,1H),2.5 3(s,3H),2.42(td,J=11.5,5.7Hz,1H),1.94(d,J=16.0Hz,1H),1.17(t,J=6.9Hz,3H). 13 C NMR (100 MHz, CDCl3), δ: 164.62, 150.54, 149.94, 136.58, 133.07, 132.68, 130.81, 130.56, 129.70, 128.86, 127.59, 127.40, 126.97, 125.73, 124.57, 123.74, 123.32, 121.92, 113.57, 113.30, 110.84, 68.78, 67.27, 39.63, 37.11, 22.01, 15.19. HRMS-ESI (m / z): calcd. 27 H 26 N3O2[M+H] + :424.2020, measured value 424.2019.

[0121]

[0122] Compound 3d (light yellow solid, yield 87%) was obtained, and TLC thin layer chromatography R f =0.26 (eluent: petroleum ether CH2Cl2). Mp 181.5-182.7℃. 1H NMR (400MHz, CDCl3), δ: 8.53 (s, 1H), 8.06 (dd, J = 7.8, 1.6Hz, 1H), 7.48–7.34 (m, 6H), 7.3 1(d,J=8.7Hz,1H),7.19–7.11(m,1H),7.08(d,J=8.0Hz,1H),7.01(d,J=8.7Hz,1H),5.80 (s,1H),4.53(dd,J=14.0,4.1Hz,1H),3.89–3.71(m,2H),3.03–2.91(m,1H),2.53(s,3H) ,2.50–2.38(m,1H),1.95(d,J=16.3Hz,1H),1.57(q,J=7.0Hz,2H),0.79(t,J=7.4Hz,3H). 13 C NMR (100 MHz, CDCl3), δ: 164.61, 150.55, 150.19, 136.55, 133.05, 132.57, 130.91, 130.55, 129.70, 128.86, 127.53, 127.33, 126.93, 125.76, 124.38, 123.76, 123.36, 121.95, 113.59, 112.95, 110.79, 73.23, 68.79, 39.62, 37.13, 22.89, 21.99, 10.49. HRMS-ESI (m / z): calcd. 28 H 28 N3O2[M+H] + :438.2177, measured value 438.2174.

[0123]

[0124] Compound 3e (light yellow solid, yield 85%) was obtained, and TLC thin layer chromatography R f =0.26 (eluent: petroleum ether CH2Cl2). Mp 169.7-170.6℃. 1H NMR (400MHz, CDCl3), δ: 8.60 (s, 1H), 8.07 (dd, J = 7.8, 1.6Hz, 1H), 7.46–7.35 (m, 6H), 7.31 (d, J = 8. 7Hz,1H),7.13(d,J=7.5Hz,1H),7.07(d,J=8.1Hz,1H),7.01(d,J=8.7Hz,1H),5.79(s,1H),4.53(d dd,J=13.0,5.2,2.0Hz,1H),3.91–3.79(m,2H),2.97(td,J=12.7,12.3,4.1Hz,1H),2.54(s,3H),2 .50–2.37(m,1H),2.00–1.91(m,1H),1.58–1.49(m,2H),1.28–1.20(m,2H),0.80(d,J=7.4Hz,3H). 13 C NMR (100 MHz, CDCl3), δ: 164.64, 150.54, 150.19, 136.56, 133.07, 132.62, 130.89, 130.54, 129.69, 128.86, 127.54, 127.34, 126.93, 125.73, 124.41, 123.71, 123.30, 121.88, 113.55, 113.03, 110.83, 71.38, 68.79, 39.64, 37.09, 31.63, 22.01, 19.06, 13.77. HRMS-ESI (m / z): calcd. 29 H 30 N3O2[M+H] + :452.2333, measured value 452.2332.

[0125]

[0126] Compound 3f (light yellow solid, yield 86%) was obtained, and TLC thin layer chromatography R f =0.26 (eluent: petroleum ether CH2Cl2). Mp 119.1-120.7℃. 1H NMR (400MHz, CDCl3), δ: 8.47 (s, 1H), 8.07 (d, J = 7.8Hz, 1H), 7.48–7.28 (m, 7H), 7.14 (t, J = 7.5 Hz,1H),7.08(d,J=8.1Hz,1H),7.02(d,J=8.7Hz,1H),5.81(s,1H),4.58–4.48(m,1H),3.92–3. 76(m,2H),2.97(td,J=12.3,4.0Hz,1H),2.53(s,3H),2.43(ddd,J=16.3,11.3,5.0Hz,1H),1. 96(d,J=15.9Hz,1H),1.55(t,J=6.8Hz,2H),1.19(q,J=4.9,3.8Hz,4H),0.81(t,J=6.7Hz,3H). 13 C NMR (100 MHz, CDCl3), δ: 164.60, 150.55, 150.24, 136.53, 133.04, 132.57, 130.90, 130.53, 129.67, 128.87, 127.53, 127.34, 126.93, 125.74, 124.46, 123.82, 123.41, 122.02, 113.62, 113.07, 110.78, 71.71, 68.79, 39.60, 37.16, 29.26, 28.06, 22.32, 21.98, 14.05. HRMS-ESI (m / z): calcd. 30 H 32 N3O2[M+H] + :466.2489, measured value 466.2487.

[0127]

[0128] Compound 3g (light yellow solid, yield 83%) was obtained, and TLC thin layer chromatography R f =0.27 (eluent: petroleum ether CH2Cl2). Mp 170.7-172.3℃. 1H NMR (400MHz, CDCl3), δ: 8.49 (s, 1H), 8.06 (dd, J=7.9, 1.6Hz, 1H), 7.46–7.37 (m, 5H), 7.35 (dt, J=5.0, 1.5Hz, 1H), 7.31 (d, J=8.7Hz,1H),7.14(td,J=7.5,1.2Hz,1H),7.11–7.05(m,1H),7.02(d,J=8.8Hz,1H),5.81(t,J=1.6Hz,1H),4.53(ddd,J=13 .0,5.2,2.1Hz,1H),3.84(ddt,J=26.0,9.2,6.5Hz,2H),2.97(ddd,J=13.0,11.4,4.1Hz,1H),2.53(s,3H),2.43(dddd,J=16 .4,11.4,5.3,1.7Hz,1H),1.96(ddt,J=16.1,4.1,1.8Hz,1H),1.57–1.51(m,2H),1.25–1.16(m,6H),0.83(t,J=6.9Hz,3H). 13 CNMR (100MHz, CDCl3), δ: 164.60, 150.55, 150.23, 136.53, 133.05, 132.56, 130.90, 130.53, 129.67, 128.86, 127.54, 127.34, 126.94, 12 5.74,124.43,123.82,123.41,122.02,113.61,113.02,110.78,71.69,68.78,39.60,37.15,31.46,29.54,25.57,22.59,21.98,14.05.

[0129]

[0130] Compound 3h (light yellow solid, yield 81%) was obtained, and TLC thin layer chromatography R f =0.27 (eluent: petroleum ether CH2Cl2). Mp 83.6-85.1℃. 1H NMR (400MHz, CDCl3), δ: 8.38 (s, 1H), 8.06 (dd, J=7.8, 1.6Hz, 1H), 7.41 (tdd, J=14.4, 11.9, 7.1Hz, 6H), 7.32 (d ,J=8.8Hz,1H),7.16(d,J=7.5Hz,1H),7.10(d,J=8.0Hz,1H),7.00(d,J=8.8Hz,1H),5.80(s,1H),4.52(ddd,J= 13.0,5.3,2.1Hz,1H),3.88–3.76(m,2H),2.97(ddd,J=13.1,11.4,4.1Hz,1H),2.53(s,3H),2.43(dddd,J=16. 3,11.4,5.3,1.8Hz,1H),2.00–1.90(m,1H),1.57–1.49(m,2H),1.21(d,J=28.6Hz,8H),0.85(t,J=7.0Hz,3H). 13 C NMR (100MHz, CDCl3), δ: 164.55, 150.53, 150.25, 136.52, 133.03, 132.53, 130.88, 130.53, 129.67, 128.87, 127.52, 127.33, 126.92, 125.7 5,124.44,123.87,123.46,122.06,113.64,113.01,110.74,71.66,6 8.79,39.58,37.19,31.76,29.57,28.92,25.82,22.55,21.96,14.11.

[0131] Example 4. Solubility test of 3 of 10-alkoxy-9-aryl evodiamine derivatives

[0132] The solubility of evodiamine and 9-aryl evodiamine derivatives was tested according to the solubility test method. The results showed that evodiamine and its derivatives were almost insoluble or insoluble in water (meaning that 1g of solute could not be completely dissolved in 10,000ml of solvent); their solubility in chloroform is shown in Table 5.

[0133] Table 5. Solubility test of 10-alkoxy-9-aryl evodiamine derivative 3

[0134]

[0135] Table 6 shows that the solubility of compound 3a obtained after the introduction of an aromatic ring at the 9-position is improved compared with 10-OH evodiamine in chloroform. After the introduction of an aromatic ring at the 9-position, if the hydrogen atom of the hydroxyl group at the 10-position is replaced by a straight-chain alkyl group, the solubility of evodiamine is also increased. Moreover, the longer the alkyl chain, the better the solubility of evodiamine. The solubility of the compound substituted by a benzyl group is worse than that of the straight-chain alkyl group.

[0136] Example 5. Antitumor Activity Test of 9-phenyl-10-alkoxyevodiamine Quinazolinone Compounds (3a-3h)

[0137] Experimental Methods: Cell lines used were human hepatocellular carcinoma HepG2 and human neuroblastoma MCF-7 cells. Tumor cells were cultured in DMEM medium supplemented with 10% fetal bovine serum; the solvent was dimethyl sulfoxide (DMSO). Antitumor activity was assessed by CCK-8 staining. Implementation: Cells in the logarithmic growth phase were used for the experiment. Cells were digested, counted, and prepared into a cell suspension. The suspension was seeded into a 96-well plate (100 μL / well) and incubated in a 37°C, 5% CO2 incubator for 24 hours. A positive control group (camptothecin and evodiamine), a blank solvent control group, and a test drug group were established. The positive control and test drug groups were administered at a concentration of 50 μmol / L per well. Each sample was plated in duplicate. After incubation for 72 hours, cell morphology was observed under a microscope. 10 μL of CCK-8 solution was added to each well, and the cells were incubated for another 4 hours. The absorbance was measured at 450 nm, and the cell inhibition rate was calculated. Statistical Analysis: Data were analyzed using SPSS 22.0 software. Student's t-test was used for comparisons between groups, with p < 0.05 considered statistically significant. All experiments were repeated three times. The results are shown in Table 6.

[0138] Table 6. Inhibitory effect of 9-phenyl-10-alkoxyevodiamine quinazolinone 3a-3h on tumor cells

[0139]

[0140] Note ** : Compared with blank solvent control, p<0.01.

[0141] The experimental results in Table 7 indicate that the 9-phenyl-10-alkoxyevodiamine quinazolinone compound, represented by Formula 3, designed and synthesized by the present invention, exhibits excellent antitumor effects against both liver cancer and neuroblastoma cells. These novel derivatives can be used to prepare antitumor drugs, particularly those against liver cancer and neuroblastoma cells.

[0142] The above is only an embodiment of the present invention, and the common knowledge such as the specific structure and characteristics of the scheme is not described in detail here. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several variations and improvements can be made, which should also be regarded as the scope of protection of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. 9-phenyl-10-alkoxyevodiamine quinazolinone derivatives, characterized in that: The structural formula is shown in Formula 3. wherein R is selected from alkyl or substituted alkyl.

2. The 9-phenyl-10-alkoxyevodiamine quinazolinone derivative according to claim 1, characterized in that: wherein R is selected from C1-C7 alkyl or substituted alkyl, including methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl.

3. The synthesis method of the 9-phenyl-10-alkoxyevodiamine quinazolinone derivative according to claim 1 or 2, wherein the synthesis route is: The method comprises the following steps: (1) using 10-hydroxyevodiamine (A) as a raw material, reacting with an alkylating agent RX in the presence of a suitable base catalyst under suitable conditions to obtain 10-alkoxyevodiamine 1; (2) reacting compound 1 with a brominating agent to obtain 9-bromo-10-alkoxyevodiamine 2; (3) reacting compound 2 with an aryl boronic acid reagent [PhB(OH)2] to obtain a 9-phenyl-10-alkoxyevodiamine quinazolinone derivative 3; wherein, In the step (1), R of the alkylating agent RX is selected from an alkyl group or a substituted alkyl group, and X is selected from I or Br.

4. The synthesis method according to claim 3, characterized in that In step (1), suitable base catalysts are selected from carbonates.

5. The synthesis method according to claim 3, characterized in that In step (2), the brominating agent is selected from liquid bromine or N-bromosuccinimide.

6. The synthesis method according to claim 3, characterized in that In step (3), the aryl boronic acid reagent is selected from phenylboronic acid; and the base catalyst is selected from carbonate.

7. The synthesis method according to claim 3, characterized in that The appropriate conditions in step (1) are: using N,N-dimethylformamide (DMF) as the reaction solvent, the reaction time is 1 to 2 hours, and the reaction temperature is 0°C to room temperature; the appropriate conditions in step (2) are: using chloroform or dichloromethane as the reaction solvent, the reaction time is 0.5 to 2 hours, and the reaction temperature is 0°C to room temperature; the appropriate conditions in step (3) are: using 1,4-dioxane as the reaction solvent, the reaction time is 12 to 24 hours, and the reaction temperature is 50°C to 80°C.

8. The synthesis method according to claim 7, characterized in that The reaction time in step (2) is 1 hour; the reaction temperature in step (3) is 60° C. to 70° C.

9. Use of the 9-phenyl-10-alkoxyevodiamine quinazolinone derivative 3 according to claim 1 or 2 in the preparation of anticancer drugs.

10. The use according to claim 9, characterized in that The cancer is liver cancer or neuroblastoma.

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