Diastereoselective preparation method of N-acetyldopamine dimer core skeleton and derivative and application of N-acetyldopamine dimer core skeleton and derivative in liver cancer resistance

Abstract

The invention discloses a diastereoselective preparation method of an N-acetyldopamine dimer core skeleton and a derivative and an application of the N-acetyldopamine dimer core skeleton and the derivative in cancer resistance in the field of medicinal chemistry, and the structural general formula of the N-acetyldopamine dimer core skeleton and the derivative is shown as a formula (I), researches show that the N-acetyldopamine dimer core skeleton and the derivative have anti-liver cancer and anti-neuroblastoma activity, can be used for preparing anti-cancer drugs, and have wide application prospects. .

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a diastereoselective preparation method of N-acetyldopamine dimer core framework and derivatives and its application in anti-liver cancer. Background Technology

[0002] The main treatments for cancer include surgery, radiotherapy, chemotherapy, and molecular targeted therapy. However, existing treatments have many limitations. Firstly, cancer treatment faces two major challenges: high metastasis rates and high recurrence rates. Secondly, most chemotherapy drugs have significant cytotoxic side effects, and the emergence of tumor drug resistance further complicates cancer treatment. Therefore, the development of novel anti-tumor drugs is crucial. With the deepening scientific research on traditional medicinal insects in my country, more and more researchers are focusing on the anti-tumor efficacy of these insects. Research results show that they can kill tumor cells at multiple targets and have the advantages of relatively low cost and low toxicity.

[0003] As a medicinal insect, the stink bug (Symplocos chinensis) is used clinically to treat tumors and various types of pain. It possesses a variety of pharmacological activities, such as antitumor activity, improvement of reproductive damage, antibacterial activity, antioxidant activity, anticoagulation, anti-ulceration, and anti-fatigue effects, as well as bioactive molecules. In recent years, medicinal chemists have paid great attention to isolating and purifying small molecule compounds from this insect.

[0004]

[0005] As shown in the above formula, many compounds containing acetyldopamine structural units have been discovered, usually existing in the form of monomers, dimers, and trimers. These dimers share a common skeleton, and the main difference lies in the presence of R / S isomers at positions 7 and 8 and in the side chain.

[0006] However, few studies have reported the synthesis of N-acetyldopamine dimers. Ding et al. synthesized the isolated natural compound (1s) via a 14-step total synthesis; however, this cumbersome synthetic process cannot provide a sufficient quantity of active molecules for pharmacological testing and SAR studies. Summary of the Invention

[0007] This invention synthesizes and prepares N-acetyldopamine dimer core framework and derivatives, providing a novel N-acetyldopamine dimer core framework and derivatives for the prevention or treatment of tumors.

[0008] One objective of this invention is to provide compounds of general formula (I) with an N-acetyldopamine dimer core framework and derivatives:

[0009] Equation (1) Wherein: R is a lower alkyl group (C<10), aromatic group or alicyclic group.

[0010] The lower alkyl groups (C<10) include methyl, ethyl, propyl, etc.; aromatic groups include phenyl, 4-methyl-phenyl, 4-nitro-phenyl, 3-fluoro-phenyl, 4-trifluoromethyl-phenyl, etc.; and alicyclic groups include cyclopropyl, etc.

[0011] R is selected from methyl, ethyl, propyl, phenyl, 4-methyl-phenyl, 4-nitro-phenyl, 3-fluoro-phenyl, 4-trifluoromethyl-phenyl or cyclopropyl.

[0012] The second objective of this invention is to provide a preparation process for the N-acetyldopamine dimer core framework and its derivatives, comprising the following steps: a. Catechol was reacted in a 50% glyoxylic acid aqueous solution, aluminum oxide, and a 5% sodium hydroxide aqueous solution at 40°C for 48 hours to yield 2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid, as shown in the following equation: ; b. 2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid was refluxed in benzyl chloride, potassium carbonate, potassium iodide, and methanol for 26 hours to obtain 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid, and the equation is shown below: ; c. 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid was refluxed in iodomethane, potassium carbonate, and acetone for 24 hours to obtain methyl 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid, as shown in the following equation: ; d. Methyl 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetate was reacted with phosphorus tribromide and toluene at room temperature for 3 hours to give methyl 2-(3,4-bis(benzyloxy)phenyl)-2-bromoacetate, and the equation is shown below: ; e. Reacting catechol in methanesulfonic anhydride, triethylamine, and dichloromethane at room temperature for 40 hours yields 2-hydroxyphenylmethanesulfonate, as shown in the following equation: ; f. 2-(3,4-bis(benzyloxy)phenyl)-2-bromoacetate and 2-hydroxyphenylmethanesulfonate were reacted in potassium carbonate and acetone at room temperature for 12 hours to give 2-(3,4-bis(benzyloxy)phenyl)-2-(2-((methanesulfonyl)oxy)phenoxy)acetate methyl ester, as shown in the following equation: ; g. 2-(3,4-bis(benzyloxy)phenyl)-2-(2-((methanesulfonyl)oxy)phenoxy)acetic acid methyl ester was reacted in potassium hydroxide and methanol at 60°C for 10 hours to give 2-(3,4-bis(benzyloxy)phenyl)-2-(2-hydroxyphenoxy)acetic acid, as shown in the following equation: ; h. 2-(3,4-bis(benzyloxy)phenyl)-2-(2-hydroxyphenoxy)acetic acid was refluxed at 40 °C for 12 h in 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, and dichloromethane to give 3-(3,4-bis(benzyloxy)phenyl)benzo[b][1,4]dioxa-2(3H)-one, as shown in the following equation: ; i. 3-(3,4-bis(benzyloxy)phenyl)benzo[b][1,4]dioxa-2(3H)-one was reacted in diisobutylaluminum hydride and dichloromethane at -30°C for 3 hours. Ethyl acetate and saturated ammonium chloride aqueous solution were added, and the mixture was slowly restored to room temperature and stirred for 12 hours to obtain 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxacyclohexane-2-ol, the equation of which is shown below: ; j. Dissolving 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-ol in a specific alcohol solution, adding a specific ammonia reagent, and reacting under specific conditions yields 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-amine, as shown in the following equation: ; k. Dissolve 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-amine and triethylamine in a specific solvent, and slowly add a specific acylation reagent, which is an acyl halide RCOX or an acid anhydride RCO-O-OCR, where X is selected from chlorine (Cl) or bromine (Br). Under specific conditions, the acylation reaction yields a benzyl-protected N-acetyldopamine dimer core skeleton and derivatives, as shown in the following equation: ; 1. The benzyl-protected IIN-acetyldopamine dimer core framework and derivatives were reacted at room temperature for 3.5 hours under palladium / carbon, hydrogen, methanol, and dichloromethane to obtain the N-acetyldopamine dimer core framework and derivatives, as shown in the following equation: .

[0013] Furthermore, the specific alcohol solution in step j refers to methanol or ethanol.

[0014] Furthermore, the specific ammonia reagent in step j refers to: ammonia water, ammonia methanol solution, or ammonia ethanol solution.

[0015] Furthermore, the specific conditions for step j are: temperature 0~80℃, reaction time 1~24 hours.

[0016] Furthermore, the specific solvent in step k refers to: dichloromethane, chloroform, tetrahydrofuran, acetonitrile, ethyl acetate, or acetone.

[0017] Furthermore, the specific acylation reagent in step k refers to an acyl halide or an anhydride; the specific conditions in step k refer to 1 to 10 equivalents of the acylation reagent and 1 to 10 equivalents of triethylamine.

[0018] A third objective of this invention is to provide the application of N-acetyldopamine dimer core framework and derivatives in the preparation of antitumor drugs.

[0019] Specifically, the anti-tumor drugs mentioned are drugs for treating liver cancer or neuroblastoma.

[0020] Further preferred, the reaction conditions for step j are: methanol as solvent, ammonia methanol solution as ammonia reagent, and stirring at room temperature for 12 hours.

[0021] Further preferred, the reaction conditions for step k are: 4 equivalents of acylation reagent, 4 equivalents of triethylamine, dichloromethane as solvent, and stirring at room temperature for 12 hours.

[0022] The present invention demonstrates through experiments that the N-acetyldopamine dimer core framework and derivatives represented by formula (1) of the present invention can inhibit the in vitro growth of two tumor cell lines, HepG2 and SK-N-SH, with medium to high inhibition rates. Detailed Implementation

[0023] The present invention will be further illustrated by specific embodiments below, but these are not intended to limit the scope of protection of the present invention. Without departing from the concept of the present invention, those skilled in the art can make improvements to the preparation method and the instruments used within the scope of the claims, and these improvements should also be considered within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

[0024] In the following examples, unless otherwise stated, the test methods are generally carried out under conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents shown are all commercially available.

[0025] Example 1: Catechol (10.00 g, 90.81 mmol) and alumina (3.70 g, 36.33 mmol) were added to a dry round-bottom flask and dissolved in 20 mL of 5% sodium hydroxide aqueous solution. 10.11 mL of 50% glyoxylic acid aqueous solution (90.81 mmol) was slowly added dropwise under an ice-salt bath. Another 100 mL of 5% sodium hydroxide aqueous solution was added, and the mixture was allowed to slowly return to room temperature before being heated and stirred in an oil bath at 40°C for 48 h. After the reaction, the pH of the reaction mixture was adjusted to 7 with 1 mol / L dilute hydrochloric acid aqueous solution. The mixture was extracted three times with ethyl acetate (to extract unreacted raw materials). The pH of the reaction mixture was then adjusted to 1, and the mixture was extracted three times with ethyl acetate (to extract the target product). Since the target product is highly water-soluble, some of it remained dissolved in the aqueous phase. The aqueous phase was filtered to remove alumina, then evaporated to dryness, dissolved in ethyl acetate, and filtered twice. The combined organic phases were dried over sodium sulfate to remove ethyl acetate, yielding a brownish-brown solid (10.80 g). No purification is required in this step; proceed directly to the next reaction.

[0026] 2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid (6.06 g, 32.91 mmol) was added to a dry round-bottom flask and dissolved in methanol (25 mL). Potassium iodide (0.27 g, 1.65 mmol) was added, followed by the addition of potassium carbonate (4.55 g × 3, 98.79 mmol) in three portions with stirring at room temperature, and then benzyl chloride (2.65 mL × 3, 69.15 mmol) was added dropwise. After each addition, the mixture was refluxed at 70 °C for 0.5 h, cooled to room temperature, and then added again. After the addition was complete, the mixture was refluxed at 70 °C for 26 h. After the reaction was complete, the solvent was removed, 50 mL of water was added, and the pH was adjusted to 1 with dilute hydrochloric acid aqueous solution (1 mol / L). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue was purified by rapid column chromatography (dichloromethane:methanol = 15:1) to give a white solid product (11.05 g). These two steps yielded a 59% productivity.

[0027] 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid (3.61 g, 9.91 mmol) was added to a dry container at 50 °C, dissolved in acetone (20 mL), followed by potassium carbonate (2.06 g, 14.90 mmol). Potassium iodide (0.62 mL, 9.91 mmol) was slowly added dropwise under stirring in an ice-salt bath. After the addition was complete, the mixture was slowly brought back to room temperature and then heated to 60 °C with stirring for 24 h. After the reaction was complete, the solvent was removed, 30 mL of water was added, and the pH was adjusted to 1 with dilute hydrochloric acid (1 mol / L). The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 4:1) to give a white solid product (3.01 g, 80% yield).

[0028] Methyl 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetate (1.54 g, 4.08 mmol) was added to a dry round-bottom flask and dissolved in toluene (8 mL). Phosphorus tribromide (0.58 mL, 6.12 mmol) was slowly added dropwise with stirring in an ice-salt bath. The mixture was then slowly brought back to room temperature for 3 h. After the reaction was complete, the mixture was quenched in ice water, extracted three times with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 8:1) to give a yellow liquid product (1.32 g, 74% yield). The product from this step is structurally unstable and should be used in the next reaction as soon as possible.

[0029] Catechol (9.00 g, 81.74 mmol) was added to a dry round-bottom flask and dissolved in dichloromethane (35 mL). Triethylamine (17.10 mL, 122.60 mmol) was then added. Methylsulfonic anhydride (15.06 g, 89.91 mmol) was added in small amounts several times with stirring in an ice-salt bath. The mixture was then slowly brought back to room temperature with stirring for 40 h. After the reaction was complete, 30 mL of water was added, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over sodium sulfate, and the residue was purified by rapid column chromatography (dichloromethane) to obtain a yellow liquid product (11.54 g, 75% yield).

[0030] Methyl 2-(3,4-bis(benzyloxy)phenyl)-2-bromoacetate (1.31 g, 2.97 mmol) was added to a dry round-bottom flask and dissolved in acetone (10 mL). Then, 2-hydroxyphenylmethanesulfonate (0.62 g, 3.26 mmol) and potassium carbonate (0.82 mg, 5.94 mmol) were added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the undissolved potassium carbonate was removed by filtration, followed by the removal of acetone. The mixture was quenched with 30 mL of water, and the pH was adjusted to 1 with dilute hydrochloric acid aqueous solution (1 mol / L). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue was purified by rapid column chromatography (petroleum ether: dichloromethane = 1:2) to obtain a yellow liquid product (1.57 g, 97% yield).

[0031] 4.60 g (8.38 mmol) of 2-(3,4-bis(benzyloxy)phenyl)-2-(2-((methanesulfonyl)oxy)phenoxy)acetic acid methyl ester was added to a dry round-bottom flask, followed by 20 mL of methanol and 2.35 g (41.92 mmol) of potassium hydroxide. The mixture was stirred at 60 °C for 10 h. After the reaction was complete, the undissolved potassium hydroxide was removed by filtration, followed by the removal of methanol. The mixture was quenched with 50 mL of water, and the pH was adjusted to 1 with dilute hydrochloric acid aqueous solution (1 mol / L). The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue was purified by rapid column chromatography (dichloromethane:methanol = 20:1) to give a white solid product (3.40 g, yield 89%).

[0032] 2-(3,4-bis(benzyloxy)phenyl)-2-(2-hydroxyphenoxy)acetic acid (4.04 g, 8.85 mmol) was added to a dry round-bottom flask and dissolved in dichloromethane (26 mL). Then, 4-dimethylaminopyridine (0.54 g, 4.43 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.48 g, 44.25 mmol) were added, and the mixture was refluxed at 40 °C with stirring for 12 hours. After the reaction was complete, 50 mL of water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over sodium sulfate, and the dichloromethane was removed to obtain a yellow solid product (3.62 g). This product is perishable by rapid column chromatography and does not require purification; it was directly added to the next reaction step.

[0033] 1.02 g (2.33 mmol) of 3-(3,4-bis(benzyloxy)phenyl)benzo[b][1,4]dioxa-2(3H)-one was added to a dry double-necked flask, and the mixture was evacuated and purged with nitrogen three times. Ultra-dry dichloromethane (30 mL) was added to dissolve the product. Diisobutylaluminum hydride (4.30 mL, 3.03 mmol) was slowly added dropwise under stirring at -30°C for 3 h. After the starting material disappeared as detected by thin-layer chromatography, the mixture was transferred to an ice-salt bath, where 1 mL of ethyl acetate and 10 mL of saturated ammonium chloride solution were added to quench the reaction. The ice-salt bath was slowly restored to room temperature, and stirring continued for 12 h. After removing the dichloromethane, 30 mL of water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried over sodium sulfate, and the residue was purified by rapid column chromatography (petroleum ether:ethyl acetate = 8:1) to give a yellow liquid product (0.40 g). The product was obtained in 39% yield from these two steps.

[0034] 1.25 g (2.83 mmol) of 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-ol was added to a dry round-bottom flask, dissolved in methanol (5 mL), and the flask was sealed. 6.20 mL of ammonia-methanol solution was added, and the mixture was stirred at room temperature for 12 hours. After freezing for 2 hours, the mixture was directly filtered to obtain a white solid (1.03 g, 82% yield). No purification was required in this step; the solid was directly added to the next reaction.

[0035] 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-amine (105 mg, 0.24 mmol) was added to a dry round-bottom flask, dissolved in dichloromethane (3.0 mL), followed by triethylamine (128 μL, 0.94 mmol) and an acylation reagent (0.90 mmol). The flask was then sealed and the reaction was stirred at room temperature. After the reaction was complete, 30 mL of water was added to quench the reaction, followed by extraction three times with dichloromethane. The organic phases were combined, dried over sodium sulfate, and the residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a benzyl-protected N-acetyldopamine core skeleton derivative.

[0036]

[0037] Table 1. Benzyl-protected N-acetyldopamine core skeleton derivatives

[0038] The benzyl-protected N-acetyldopamine core skeleton derivative was placed in a dry PTFE gated reaction flask with a side tube, dissolved in methanol (2 mL) and dichloromethane (2 mL), and then palladium on carbon (25%) was added. The flask was quickly sealed, purged with nitrogen three times, and then purged with hydrogen three times. A hydrogen balloon was inserted, and the reaction was allowed to proceed for 3.5 h. After the reaction was completed, palladium on carbon and dichloromethane were removed by filtration. The residue was purified by rapid column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain the N-acetyldopamine dimer core skeleton derivative (compound 1).

[0039]

[0040] Table 2. Derivatives of N-acetyldopamine dimer core skeleton

[0041] Example 2: Log-cycle human hepatocellular carcinoma HepG2 cells and human neuroblastoma cells SK-N-SH cells were used in the experiment. Cells were digested, counted, and prepared into a cell suspension, then seeded into 96-well plates (100 μL / well) and cultured at 37℃ in a 5% CO2 incubator for 24 h. A 50 μmol / L concentration of the test substance was added to each well. A solvent control group, an experimental group, and a positive control (paclitaxel and L-norepinephrine) were also established, with three replicates per group. After culturing the plates in an incubator for 72 h, 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 2 h. Absorbance was measured at 450 nm, and the cell inhibition rate was calculated. The results are shown in Table 3 below.

[0042] Table 3. Inhibition rate (%) of N-acetyldopamine dimer core backbone derivatives on SK-N-SH and HepG2 tumor cells

[0043] Appendix: Compound NMR Data

[0044] Intermediate B (92%), white solid. f = 0.20 (CH2Cl2: MeOH = 15 : 1). 1 H NMR (400MHz, DMSO-d6)δ 7.44 – 7.36 (m, 4H), 7.36 – 7.23 (m, 7H), 6.88 (s, 2H), 5.00(d, J = 23.0 Hz, 4H), 4.79 – 4.48 (m, 1H). 13C NMR (101 MHz, DMSO-d6)δ 148.37,147.42, 137.95, 137.89, 128.76, 128.70, 128.07, 127.80, 114.33, 70.65.

[0045] Intermediate C (80%), white solid. R f = 0.17 (PE : EA = 4 : 1). 1 H NMR (400 MHz,Chloroform-d)δ 7.46 (td, J = 6.4, 3.3 Hz, 4H), 7.41 – 7.28 (m, 6H), 7.02 (d, J = 1.9 Hz, 1H), 6.97 – 6.89 (m, 2H), 5.16 (d, J = 4.1 Hz, 4H), 5.08 (s, 1H), 3.69 (d, J = 1.1 Hz, 3H), 3.51 (s, 1H). 13 C NMR (101 MHz, Chloroform-d)δ 174.16,149.10, 148.92, 137.14, 137.07, 131.37, 128.54, 128.51, 127.86, 127.42,127.25, 119.88, 114.59, 113.04, 72.55, 71.14, 71.12, 53.01.

[0046] Intermediate D (74%), a yellow liquid. R f = 0.60 (PE : EA = 4 : 1). 1 H NMR (400 MHz, Chloroform-d)δ 7.50 – 7.41 (m, 4H), 7.40 – 7.29 (m, 6H), 7.22 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.3, 2.1 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.28 (d, J = 6.7Hz, 1H), 5.17 (d,J = 7.6 Hz, 4H), 3.72 (d, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 168.80, 149.95, 149.00, 136.92, 136.89, 128.57, 128.52, 128.43,127.92, 127.50, 127.18, 122.01, 115.24, 114.18, 71.31, 71.07, 53.31, 46.70.

[0047] Intermediate E (75%) is a yellow liquid. f = 0.60 (DCM). 1 H NMR (400 MHz, Chloroform-d)δ7.23 (dd, J = 8.1, 1.6 Hz, 1H), 7.15 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.99 (dd, J = 8.2, 1.6 Hz, 1H), 6.89 (ddd, J = 8.1, 7.4, 1.6 Hz, 1H), 6.64 (s, 1H), 3.20 (s, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 148.13, 136.70, 128.92, 123.53,121.45, 118.78, 37.42.

[0048] Intermediate F (97%) is a yellow liquid. R f = 0.78 (PE : DCM = 1 : 2). 1 H NMR (400 MHz, Chloroform-d)δ 7.45 (d, J = 7.5 Hz, 4H), 7.39 – 7.29 (m, 7H), 7.18 – 7.13 (m,2H), 7.06 – 6.97 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.81 (dd, J= 8.3, 1.5 Hz,1H), 5.56 (s, 1H), 5.18 (d, J = 12.0 Hz, 4H), 3.69 (d, J = 1.1 Hz, 3H), 3.19(d, J = 1.0 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d)δ 169.63, 149.75, 148.99,148.84, 141.06, 139.00, 136.89, 136.86, 128.56, 128.50, 128.48, 128.12,127.92, 127.86, 127.36, 127.21, 125.25, 124.41, 122.54, 120.54, 115.26,114.52, 113.37, 71.03, 52.73, 52.71.

[0049] Intermediate G (89%), white solid. R f = 0.22 (CH2Cl2 : MeOH = 20 : 1). 1 H NMR (400MHz, DMSO-d6)δ 7.48 (d, J = 7.5 Hz, 2H), 7.44 (d, J = 7.3 Hz, 2H), 7.40 (d, J =7.1 Hz, 2H), 7.38 – 7.31 (m, 5H), 7.08 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.4Hz, 1H), 6.90 – 6.77 (m, 3H), 6.65 (t, J = 7.6 Hz, 1H), 5.15 – 5.03 (m, 5H). 13CNMR (101 MHz, DMSO-d6)δ 174.56, 150.08, 148.33, 148.14, 147.46, 137.85,137.74, 133.06, 128.84, 128.28, 128.19, 127.91, 123.75, 120.89, 119.43,117.11, 114.70, 114.50, 84.96, 70.87, 70.60.

[0050] Intermediate H (93%), a yellow solid. R f = 0.90 (PE : EA = 4 : 1). 1 H NMR (400 MHz,Chloroform-d)δ 7.43 – 7.30 (m, 10H), 7.10 – 6.97 (m, 5H), 6.92 – 6.87 (m,2H), 5.65 (s, 1H), 5.13 (d, J = 5.0 Hz, 4H). 13 C NMR (101 MHz, Chloroform-d)δ163.59, 149.79, 149.04, 141.47, 141.05, 136.86, 136.81, 128.56, 127.92,127.33, 127.18, 125.87, 125.54, 123.33, 120.36, 117.75, 117.12, 114.36,113.44, 71.21, 71.00.

[0051] Intermediate I (39%, dr = 1:1), a yellow liquid. f = 0.43 (PE : EA = 3 : 1). 1 H NMR(400 MHz, CDCl3)δ 7.32 (dt, J = 13.7, 6.1 Hz, 3H), 7.26 – 7.04 (m, 7H), 6.96 –6.56 (m, 7H), 5.26 (dd, J = 101.2, 5.4 Hz, 1H), 5.07 – 4.90 (m, 4H), 4.81 –4.56 (m, 1H), 3.65 – 3.20 (m, 1H).13 C NMR (101 MHz, CDCl3)δ 149.38, 149.33,149.01, 148.90, 143.22, 142.65, 141.39, 140.25, 137.13, 137.11, 137.08,137.03, 129.16, 128.58, 128.54, 127.94, 127.91, 127.57, 127.53, 127.31,127.29, 122.55, 122.19, 122.13, 122.09, 120.64, 120.22, 117.85, 117.40, 117.36, 117.08, 114.78, 114.72, 114.10, 113.88, 92.74, 91.13, 76.45, 71.41, 71.36, 71.25, 71.19.

[0052] Intermediate J (82%, dr = 1:1), white solid. R f = 0.28 (PE : DCM = 1 : 3), 1 H NMR(400 MHz, CDCl3)δ 7.46 – 7.28 (m, 10H), 7.06 – 6.77 (m, 7H), 5.18 – 5.06 (m,4H), 4.79 (d, J = 6.2 Hz, 1H), 4.62 (d, J = 6.3 Hz, 1H), 2.01 (s, 2H). 13 C NMR(101 MHz, CDCl3)δ 149.40, 149.34, 149.03, 148.91, 143.19, 142.62, 141.34,140.23, 137.12, 137.07, 137.02, 129.11, 128.56, 128.53, 128.40, 127.90,127.54, 127.50, 127.27, 122.56, 122.19, 122.13, 122.09, 120.60, 120.17,117.85, 117.39, 117.35, 117.08, 114.78, 114.72, 114.07, 113.85, 92.72, 91.13, 71.40, 71.35, 71.24, 71.18.

[0053] Intermediate IIa-cis (29%), white solid. R f = 0.67 (PE : EA = 2 : 1). 1 H NMR (400MHz, CDCl3)δ 7.47 – 7.42 (m, 4H), 7.40 – 7.33 (m, 4H), 7.33 – 7.28 (m, 2H), 7.04 – 6.99 (m, 2H), 6.99 – 6.90 (m, 5H), 6.15 (d, J = 4.7 Hz, 2H), 5.18 (d, J = 8.0 Hz, 4H), 5.13 (s, 1H), 1.78 (s, 3H). 13 C NMR (101 MHz, CDCl3)δ 170.33,149.13, 149.02, 142.64, 140.96, 136.97, 136.94, 128.56, 128.54, 127.95,127.91, 127.81, 127.36, 127.27, 122.99, 121.93, 118.87, 118.27, 117.44,114.84, 112.54, 74.99, 71.37, 71.14, 23.22.

[0054] Intermediate IIa-trans (58%), white solid. R f = 0.52 (PE : EA = 2 : 1). 1 H NMR (400MHz, CDCl3)δ 7.46 – 7.39 (m, 4H), 7.38 – 7.27 (m, 6H), 6.99 (d, J = 1.7 Hz,1H), 6.95 – 6.85 (m, 6H), 6.29 (d, J = 9.6 Hz, 1H), 6.03 (dd, J = 9.6, 5.1 Hz, 1H), 5.12 (d, J = 10.7 Hz, 4H), 4.86 (d, J = 5.1 Hz, 1H), 1.91 (s, 3H). 13C NMR(101 MHz, CDCl3)δ 169.86, 149.44, 148.94, 142.16, 141.60, 136.96, 136.93,128.51, 128.50, 127.86, 127.41, 127.23, 122.30, 122.07, 120.56, 117.66,117.23, 114.62, 113.78, 75.49, 71.27, 71.04, 23.33.

[0055] Intermediate IIb-trans (90%, dr = 20 : 1), white solid. f = 0.31 (PE : DCM = 1 :3). 1 H NMR (400 MHz, CDCl3)δ 7.66 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.39 (d, J = 7.0 Hz, 5H), 7.33 (t, J = 7.7 Hz, 5H), 7.30 – 7.24 (m, 2H), 7.05(s, 1H), 6.99 – 6.93 (m, 3H), 6.89 (d, J = 9.3 Hz, 4H), 6.22 (dd, J = 9.5, 5.4Hz, 1H), 5.08 (s, 4H), 4.99 (d, J = 5.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3)δ167.09, 149.45, 149.05, 142.27, 141.73, 136.95, 136.91, 133.24, 132.26,128.67, 128.53, 128.50, 128.48, 127.85, 127.83, 127.42, 127.22, 127.20,122.36, 122.08, 120.63, 117.69, 117.28, 114.68, 113.76, 76.21, 71.31, 71.01.

[0056] Intermediate IIc-cis (27%), white solid. R f = 0.58 (PE : EA = 3 : 1). 1 H NMR (400MHz, CDCl3)δ 7.48 – 7.26 (m, 10H), 7.04 – 6.89 (m, 7H), 6.18 (dd, J = 9.4, 2.0Hz, 1H), 6.07 (d, J = 9.4 Hz, 1H), 5.22 – 5.12 (m, 5H), 2.00 (tt, J = 15.5, 7.8Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ 173.93, 149.06,149.03, 142.64, 141.00, 136.96, 136.94, 128.56, 128.53, 127.94, 127.92,127.90, 127.37, 127.25, 122.97, 121.89, 118.86, 118.26, 117.42, 114.87,112.52, 74.92, 71.37, 71.13, 29.37, 9.20.

[0057] Intermediate IIc-trans (55%), white solid. R f = 0.35 (PE : EA = 3 : 1). 1 H NMR (400MHz, CDCl3)δ 7.41 (d, J = 7.0 Hz, 4H), 7.37 – 7.27 (m, 6H), 6.99 (d, J = 1.6Hz, 1H), 6.94 – 6.86 (m, 6H), 6.15 (d, J = 9.6 Hz, 1H), 6.02 (dd, J = 9.6, 5.3Hz, 1H), 5.12 (d, J = 10.7 Hz, 4H), 4.84 (d, J = 5.3 Hz, 1H), 2.11 (ddt, J=18.1, 15.6, 7.9 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3)δ173.40, 149.42, 148.98, 142.26, 141.71, 136.97, 136.94, 128.56, 128.50,127.86, 127.85, 127.41, 127.20, 122.27, 122.02, 120.58, 117.66, 117.21,114.67, 113.76, 71.26, 71.05, 29.52, 9.23.

[0058] Intermediate IId-trans (76%, dr = 20 : 1), white solid. f = 0.53 (PE : DCM = 1 :3). 1 H NMR (400 MHz, CDCl3)δ 7.57 (d, J = 8.0 Hz, 2H), 7.41 – 7.36 (m, 4H), 7.34(t, J = 1.9 Hz, 1H), 7.33 (q, J = 1.6 Hz, 2H), 7.31 – 7.26 (m, 3H), 7.17 (d, J =7.9 Hz, 2H), 7.05 (d, J = 2.1 Hz, 1H), 6.98 – 6.94 (m, 2H), 6.92 – 6.86 (m,5H), 6.22 (dd, J = 9.5, 5.4 Hz, 1H), 5.09 (d, J = 12.5 Hz, 4H), 4.99 (d, J = 5.4Hz, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3)δ 166.92, 149.45, 149.07,142.85, 142.27, 141.75, 136.98, 136.94, 130.39, 129.32, 128.61, 128.48,128.46, 127.83, 127.81, 127.41, 127.23, 127.20, 122.33, 122.04, 120.61,117.70, 117.25, 114.72, 113.80, 71.33, 71.05, 21.51.

[0059] Intermediate IIe-trans (85%, dr = 20 : 1), white solid. f = 0.39 (PE : DCM = 1 :4). 1 H NMR (400 MHz, CDCl3)δ 7.43 – 7.38 (m, 4H), 7.38 – 7.28 (m, 6H), 6.99 (d, J = 1.7 Hz, 1H), 6.95 – 6.86 (m, 6H), 6.16 (d, J = 9.7 Hz, 1H), 6.02 (dd, J =9.7, 5.5 Hz, 1H), 5.12 (d, J = 8.9 Hz, 4H), 4.82 (d, J = 5.5 Hz, 1H), 2.13 –2.00 (m, 2H), 1.52 (qd, J = 7.4, 1.2 Hz, 2H), 0.78 (t, J = 7.4 Hz, 3H). 13 C NMR(101 MHz, CDCl3)δ 172.63, 149.46, 149.04, 142.31, 141.77, 136.98, 136.94,128.56, 128.50, 127.87, 127.84, 127.42, 127.18, 122.26, 122.00, 120.66,117.63, 117.20, 114.71, 113.81, 75.59, 71.28, 71.08, 38.40, 18.67, 13.44.

[0060] Intermediate IIf-trans (77%, dr = 50 : 1), yellow solid. R f = 0.23 (PE : DCM = 1 :3). 1 H NMR (400 MHz, CDCl3)δ 8.22 – 8.14 (m, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.38(d, J = 6.8 Hz, 4H), 7.35 – 7.26 (m, 6H), 7.04 (d, J = 2.0 Hz, 1H), 6.99 – 6.92(m, 3H), 6.92 – 6.87 (m, 4H), 6.18 (dd, J = 9.4, 5.3 Hz, 1H), 5.10 (d, J = 10.3Hz, 4H), 4.96 (d, J = 5.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3)δ 165.16, 149.85,149.60, 149.10, 142.15, 141.45, 138.67, 136.79, 136.78, 128.51, 128.41,128.15, 127.92, 127.41, 123.84, 122.52, 122.37, 120.65, 117.60, 117.40,114.55, 113.78, 76.31, 71.39, 70.99.

[0061] Intermediate IIg-trans (85%, dr = 25 : 1), white solid. f = 0.20 (PE : DCM = 1 :3). 1 H NMR (400 MHz, CDCl3)δ 7.43 – 7.38 (m, 4H), 7.35 (dd, J = 7.0, 1.5 Hz,3H), 7.33 – 7.30 (m, 2H), 7.28 (d, J = 7.1 Hz, 1H), 7.00 (d, J= 1.9 Hz, 1H), 6.95 – 6.91 (m, 1H), 6.89 (ddt, J = 6.3, 4.7, 2.6 Hz, 5H), 6.46 (d, J = 9.6 Hz, 1H), 6.06 (dd, J = 9.6, 5.0 Hz, 1H), 5.11 (d, J = 14.2 Hz, 4H), 4.91 (d, J = 4.9Hz, 1H), 1.26 (tt, J = 8.1, 4.5 Hz, 1H), 1.00 (ddt, J = 9.8, 4.9, 2.9 Hz, 1H),0.91 (tdd, J = 7.0, 4.5, 2.5 Hz, 1H), 0.73 (tdd, J = 8.7, 6.3, 3.4 Hz, 2H). 13 CNMR (101 MHz, CDCl3)δ 173.55, 149.36, 148.97, 142.15, 141.66, 137.00, 136.95,128.69, 128.50, 128.48, 127.84, 127.42, 127.20, 122.28, 122.01, 120.51,117.77, 117.22, 114.66, 113.76, 75.42, 71.29, 71.06, 14.81, 8.22, 8.16.

[0062] Intermediate IIh-trans (88%, dr = 25 : 1), white solid. f = 0.49 (PE : DCM = 1 :3). 1 H NMR (400 MHz, CDCl3)δ 7.42 – 7.36 (m, 6H), 7.36 – 7.31 (m, 4H), 7.31 –7.27 (m, 3H), 7.21 – 7.16 (m, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.98 – 6.94 (m,2H), 6.92 – 6.86 (m, 5H), 6.19 (dd, J= 9.4, 5.4 Hz, 1H), 5.10 (d, J = 10.4 Hz, 4H), 4.98 (d, J = 5.4 Hz, 1H). 13 C NMR (101 MHz, CDCl3)δ 165.81, 163.87, 161.40,149.52, 149.09, 142.22, 141.60, 136.91, 136.87, 135.48, 135.41, 130.44,130.36, 128.49, 128.37, 127.86, 127.85, 127.40, 127.20, 122.69, 122.41,122.18, 120.62, 119.41, 119.20, 117.66, 117.32, 114.77, 114.68, 114.54, 113.76, 76.25, 71.33, 71.03.

[0063] Intermediate IIi-trans (92%, dr = 25 : 1), white solid. R f = 0.61 (PE : DCM = 1 :3). 1 H NMR (400 MHz, CDCl3)δ 7.72 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 7.4 Hz, 4H), 7.31 (q, J = 9.0, 8.0 Hz, 6H), 7.05 (s, 1H), 7.01 –6.87 (m, 7H), 6.19 (dd, J = 9.3, 5.3 Hz, 1H), 5.10 (d, J = 11.3 Hz, 4H), 4.97(d, J = 5.4 Hz, 1H). 13C NMR (101 MHz, CDCl3)δ 165.88, 149.54, 149.08, 142.21,141.55, 136.85, 136.81, 136.47, 128.50, 128.26, 127.88, 127.69, 127.40,127.19, 125.72, 125.68, 122.46, 122.26, 120.63, 117.62, 117.36, 114.57,113.74, 71.34, 70.97.

[0064] Compound Ia-cis (95%) is a white solid. R f = 0.14 (PE : EA = 1 : 1),Mp195.8 -196.8 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 8.96 (s, 2H), 8.73 (d, J = 9.8 Hz, 1H),7.02 – 6.95 (m, 1H), 6.89 (d, J = 2.3 Hz, 4H), 6.77 (dd, J = 8.1, 2.0 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.95 (dd, J = 9.8, 2.0 Hz, 1H), 5.12 (d, J = 2.0 Hz, 1H), 1.75 (s, 3H). 13 C NMR (101 MHz, DMSO-d6)δ 170.81, 145.73, 145.36, 143.84,141.51, 126.83, 122.58, 121.70, 118.19, 117.93, 117.84, 115.61, 114.73,76.06, 75.57, 22.79.HRMS-ESI(m / z): calcd for C 16 H 15 NO5[M+Na] + : 324.0843, found324.0839.

[0065] Compound Ia-trans (94%) is a white solid. Rf = 0.17 (PE : EA = 1 : 1),Mp101.7 -102.8 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.04 (s, 2H), 8.91 (d, J = 9.6 Hz, 1H), 6.94 – 6.81 (m, 4H), 6.77 (s, 1H), 6.73 – 6.63 (m, 2H), 5.57 (t, J = 8.4 Hz, 1H), 4.71 (d, J = 7.4 Hz, 1H), 1.75 (s, 3H). 13 C NMR (101 MHz, DMSO-d6)δ 169.94,146.21, 145.50, 143.27, 142.66, 127.20, 122.17, 121.86, 119.48, 117.24,115.69, 115.22, 77.03, 76.58, 23.07.HRMS-ESI(m / z): calcd for C 16 H 15 NO5[M+Na] + :324.0843, found 324.0836.

[0066] Compound Ib-trans (88%, dr = 20 : 1), white solid. R f = 0.33 (PE : EA = 1 : 1),Mp215.4 - 216.5 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.36 (d, J = 9.6 Hz, 1H), 9.02(s, 2H), 7.73 (dd, J = 7.0, 1.6 Hz, 2H), 7.56 – 7.50 (m, 1H), 7.44 (dd, J =8.3, 6.7 Hz, 2H), 6.99 – 6.93 (m, 2H), 6.91 – 6.84 (m, 3H), 6.77 (dd, J = 8.2, 2.0 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.77 (dd,J = 9.5, 7.9 Hz, 1H), 4.93 (d, J = 7.9 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6)δ 166.71, 146.29, 145.58, 143.54,142.89, 133.66, 132.52, 128.94, 127.89, 127.23, 122.30, 121.97, 119.60,117.33, 117.27, 115.75, 115.33, 78.15, 76.58.HRMS-ESI(m / z): calcd for C 21 H 17 NO5[M+Na] + 386.0999, found 386.1000.

[0067] Compound Ic-cis (96%) is a white solid. R f = 0.49 (PE : EA = 1 : 1),Mp100.0 -100.8 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 8.98 (s, 2H), 8.65 (d, J = 9.8 Hz, 1H),7.00 – 6.95 (m, 1H), 6.88 (s, 4H), 6.79 – 6.74 (m, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.94 (dd, J = 9.8, 1.9 Hz, 1H), 5.12 (d, J = 2.1 Hz, 1H), 2.03 (q, J = 7.6Hz, 2H), 0.80 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, DMSO-d6)δ 174.51, 145.75,145.38, 143.88, 141.58, 126.87, 122.60, 121.71, 118.30, 117.97, 117.84,115.58, 114.85, 76.16, 75.63, 28.37, 9.93.HRMS-ESI(m / z): calcd for C 17 H 17 NO5[M+Na] + : 338.0999, found 338.0995.

[0068] Compound Ic-trans (94%) is a white solid. R f = 0.37 (PE : EA = 1 : 1),Mp176.5 -177.3 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.13 – 8.90 (m, 2H), 8.80 (d, J = 9.7 Hz, 1H), 6.90 (ddt, J = 11.7, 7.7, 3.6 Hz, 2H), 6.84 (ddd, J = 6.6, 3.0, 1.7 Hz,2H), 6.77 (d, J = 1.8 Hz, 1H), 6.71 – 6.65 (m, 2H), 5.56 (dd, J = 9.4, 7.4 Hz, 1H), 4.72 (d, J = 7.5 Hz, 1H), 2.00 (th, J = 15.2, 7.5 Hz, 2H), 0.85 (t, J = 7.5Hz, 3H). 13 C NMR (101 MHz, DMSO-d6)δ 173.58, 146.21, 145.51, 143.36, 142.77,127.24, 122.20, 121.89, 119.50, 117.27, 115.67, 115.26, 77.22, 76.69, 28.91,9.81.HRMS-ESI(m / z): calcd for C 17 H 17NO5[M+Na] + : 338.0999, found 338.0993.

[0069] Compound Id-trans (92%, dr = 20 : 1), white solid. R f = 0.48 (PE : EA = 1 : 1),Mp 210.5 - 211.3 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.30 (d, J = 9.6 Hz, 1H), 9.06(s, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 6.96 (dt, J = 6.6, 3.0 Hz, 2H), 6.87 (dq, J = 9.1, 3.7, 2.4 Hz, 3H), 6.79 – 6.73 (m, 1H), 6.68(d, J = 8.1 Hz, 1H), 5.76 (t, J = 8.7 Hz, 1H), 4.93 (d, J = 8.0 Hz, 1H), 2.31(s, 3H). 13 C NMR (101 MHz, DMSO-d6)δ 166.44, 146.23, 145.52, 143.49, 142.86,142.60, 130.74, 129.44, 127.92, 127.20, 122.27, 121.92, 119.56, 117.30,117.24, 115.67, 115.25, 78.09, 76.51, 21.44.HRMS-ESI(m / z):calcd for C 22 H 19 NO5[M+Na] + : 400.1156, found 400.1149.

[0070] Compound Ie-trans (93%, dr = 20 : 1), white solid. R f= 0.43 (PE : EA = 1 : 1),Mp144.7 - 145.7 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.02 (s, 2H), 8.82 (d, J = 9.5Hz, 1H), 6.93 – 6.82 (m, 4H), 6.76 (s, 1H), 6.67 (s, 2H), 5.56 (t, J = 8.6 Hz, 1H), 4.70 (d, J = 7.6 Hz, 1H), 1.95 (hept, J = 7.1 Hz, 2H), 1.34 (h, J = 7.2 Hz, 2H), 0.62 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6)δ 172.62, 146.19,145.47, 143.34, 142.75, 127.09, 122.19, 121.86, 119.54, 117.25, 115.57,115.21, 77.12, 76.71, 37.63, 18.72, 13.59.HRMS-ESI(m / z): calcd for C 18 H 19 NO5[M+Na] + 352.1154, found 352.1148.

[0071] The compound, If-trans (93%, dr = 50 : 1), is a white solid. f = 0.19 (PE : EA = 1 : 1),Mp201.7 - 202.5 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.00 (s, 2H), 8.82 (d, J = 9.7Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 6.93 (td, J = 7.0, 2.4 Hz, 2H), 6.89 – 6.81(m, 3H), 6.74 (d, J= 8.2 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 8.2Hz, 2H), 5.75 (s, 2H), 5.72 (d, J = 9.4 Hz, 1H), 4.92 (d, J = 8.0 Hz, 1H). 13 CNMR (101 MHz, DMSO-d6)δ 166.41, 152.90, 146.20, 145.51, 143.55, 143.07,129.69, 127.51, 122.21, 121.77, 119.90, 119.61, 117.23, 115.68, 115.33,112.94, 78.18, 76.64.HRMS-ESI(m / z): calcd for C 21 H 18 N₂O₅[M+Na] + : 401.1108, found 401.1105.

[0072] Compound Ig-trans (99%, dr = 25 : 1), white solid. R f = 0.25 (PE : EA = 1 : 1),Mp164.6 - 165.2 ℃. 1 H NMR (400 MHz, DMSO-d6)δ 9.11 (d, J = 9.6 Hz, 1H), 9.04(s, 2H), 6.90 (tt, J = 6.8, 3.3 Hz, 2H), 6.85 (dq, J = 5.6, 3.3, 2.0 Hz, 2H), 6.77 (s, 1H), 6.72 – 6.66 (m, 2H), 5.64 – 5.56 (m, 1H), 4.78 (d, J = 7.3 Hz, 1H), 1.48 (td, J = 7.7, 3.9 Hz, 1H), 0.73 – 0.64 (m, 2H), 0.64 – 0.56 (m, 2H). 13C NMR (101 MHz, DMSO-d6)δ 173.67, 146.26, 145.55, 143.32, 142.71, 127.34,122.21, 121.89, 119.55, 117.30, 117.26, 115.76, 115.32, 77.09, 76.64, 14.10,7.78, 7.43.HRMS-ESI(m / z): calcd for C 18 H 17 NO5[M+Na] + : 350.0999, found 350.0999.

[0073] Compound Ih-trans (97%, dr = 25 : 1), white solid. R f = 0.44 (PE : EA = 1 :1),Mp189.3 - 189.6 ℃, 1 H NMR (400 MHz, DMSO-d6)δ 9.47 (d, J = 9.5 Hz, 1H),9.05 (s, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.40 (td, J = 8.5, 2.8 Hz, 1H), 6.96 (dt, J = 6.4, 2.9 Hz, 2H), 6.90 – 6.84 (m, 3H), 6.76 (dd, J =8.2, 2.0 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.80 – 5.74 (m, 1H), 4.91 (d, J =7.9 Hz, 1H). 13C NMR (101 MHz, DMSO-d6)δ 165.37, 163.58, 161.15, 146.32,145.60, 143.50, 142.78, 135.94, 135.87, 131.29, 131.21, 127.09, 124.11,122.33, 122.05, 119.58, 119.41, 117.36, 117.28, 115.76, 115.31, 114.78,114.56, 78.14, 76.53.HRMS-ESI(m / z): calcd for C 21 H 16 FNO5[M+Na] + : 404.0905, found 404.0897.

[0074] Compound Ii-trans (95%, dr = 25 : 1), white solid. R f = 0.68 (PE : EA = 1 : 1),Mp107.6 - 108.2 ℃, 1 H NMR (400 MHz, DMSO-d6)δ 9.63 (d, J = 9.4 Hz, 1H), 9.03(s, 2H), 7.92 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 6.96 (dq, J = 8.1,3.4, 2.8 Hz, 2H), 6.92 – 6.85 (m, 3H), 6.76 (dd, J = 8.2, 2.0 Hz, 1H), 6.68(d, J = 8.1 Hz, 1H), 5.79 (t, J = 8.6 Hz, 1H), 4.93 (d, J = 7.9 Hz, 1H). 13C NMR(101 MHz, DMSO-d6)δ 165.61, 146.33, 145.60, 143.48, 142.74, 137.34, 132.45,132.13, 128.81, 127.03, 126.06, 126.02, 125.60, 122.90, 122.35, 122.09,119.60, 117.38, 117.29, 115.75, 115.27, 78.11, 76.51.HRMS-ESI(m / z): calcd forC 22 H 16 F3NO5[M+Na] + : 454.0873, found 454.0874. The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. The N-acetyldopamine dimer core framework and its derivatives, characterized in that, Its structural formula is (I). Wherein: R is a lower alkyl group (C<10), selected from aromatic or alicyclic groups.

2. The N-acetyldopamine dimer core framework and derivatives according to claim 1, characterized in that: R is selected from methyl, ethyl, propyl, phenyl, 4-methyl-phenyl, 4-nitro-phenyl, 3-fluoro-phenyl, 4-trifluoromethyl-phenyl or cyclopropyl.

3. The preparation process of the N-acetyldopamine dimer core framework and derivatives according to claim 1, characterized in that, Includes the following steps: a. Catechol was reacted in a 50% glyoxylic acid aqueous solution, aluminum oxide, and a 5% sodium hydroxide aqueous solution at 40°C for 48 hours to yield 2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid, as shown in the following equation: ； b. 2-(3,4-dihydroxyphenyl)-2-hydroxyacetic acid was refluxed in benzyl chloride, potassium carbonate, potassium iodide, and methanol for 26 hours to obtain 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid, and the equation is shown below: ； c. 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid was refluxed in iodomethane, potassium carbonate, and acetone for 24 hours to obtain methyl 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetic acid, as shown in the following equation: ； d. Methyl 2-(3,4-bis(benzyloxy)phenyl)-2-hydroxyacetate was reacted with phosphorus tribromide and toluene at room temperature for 3 hours to give methyl 2-(3,4-bis(benzyloxy)phenyl)-2-bromoacetate, and the equation is shown below: ； e. Reacting catechol in methanesulfonic anhydride, triethylamine, and dichloromethane at room temperature for 40 hours yields 2-hydroxyphenylmethanesulfonate, as shown in the following equation: ； f. 2-(3,4-bis(benzyloxy)phenyl)-2-bromoacetate and 2-hydroxyphenylmethanesulfonate were reacted in potassium carbonate and acetone at room temperature for 12 hours to give 2-(3,4-bis(benzyloxy)phenyl)-2-(2-((methanesulfonyl)oxy)phenoxy)acetate methyl ester, as shown in the following equation: ； g. 2-(3,4-bis(benzyloxy)phenyl)-2-(2-((methanesulfonyl)oxy)phenoxy)acetic acid methyl ester was reacted in potassium hydroxide and methanol at 60°C for 10 hours to give 2-(3,4-bis(benzyloxy)phenyl)-2-(2-hydroxyphenoxy)acetic acid, as shown in the following equation: ； h. 2-(3,4-bis(benzyloxy)phenyl)-2-(2-hydroxyphenoxy)acetic acid was refluxed at 40 °C for 12 h in 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, and dichloromethane to give 3-(3,4-bis(benzyloxy)phenyl)benzo[b][1,4]dioxa-2(3H)-one, as shown in the following equation: ； i. 3-(3,4-bis(benzyloxy)phenyl)benzo[b][1,4]dioxa-2(3H)-one was reacted in diisobutylaluminum hydride and dichloromethane at -30°C for 3 hours. Ethyl acetate and saturated ammonium chloride aqueous solution were added, and the mixture was slowly restored to room temperature and stirred for 12 hours to obtain 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxacyclohexane-2-ol, the equation of which is shown below: ； j. Dissolving 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-ol in a specific alcohol solution, adding a specific ammonia reagent, and reacting under specific conditions yields 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-amine, as shown in the following equation: ； k. Dissolve 3-(3,4-bis(benzyloxy)phenyl)-2,3-dihydrobenzo[b][1,4]dioxane-2-amine and triethylamine in a specific solvent, and slowly add a specific acylation reagent, which is an acyl halide RCOX or an acid anhydride RCO-O-OCR, where X is selected from chlorine (Cl) or bromine (Br). Under specific conditions, the acylation reaction yields a benzyl-protected N-acetyldopamine dimer core skeleton and derivatives, as shown in the following equation: ； 1. The benzyl-protected IIN-acetyldopamine dimer core framework and derivatives were reacted at room temperature for 3.5 hours under palladium / carbon, hydrogen, methanol, and dichloromethane to obtain the N-acetyldopamine dimer core framework and derivatives, as shown in the following equation: 。 4. The preparation process according to claim 3, characterized in that, The specific alcohol solution in step j refers to methanol or ethanol.

5. The preparation method according to claim 3, characterized in that, The specific ammonia reagent in step j refers to: ammonia water, ammonia methanol solution, or ammonia ethanol solution.

6. The preparation method according to claim 3, characterized in that, The specific conditions for step j are: temperature 0-80℃, reaction time 1-24 hours.

7. The preparation method according to claim 3, characterized in that, The specific solvent in step k refers to: dichloromethane, chloroform, tetrahydrofuran, acetonitrile, ethyl acetate, or acetone.

8. The preparation method according to claim 3, characterized in that, The specific acylation reagent in step k refers to an acyl halide or an acid anhydride; the specific conditions in step k refer to 1 to 10 equivalents of the acylation reagent and 1 to 10 equivalents of triethylamine.

9. The use of the N-acetyldopamine dimer core backbone and derivatives according to any one of claims 1 or 2 in the preparation of antitumor drugs.

10. The application according to claim 9, characterized in that, The anti-tumor drugs mentioned are drugs for treating liver cancer or neuroblastoma.

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