Cycloartemisinin 5-glycosylated derivatives, processes for their preparation and uses thereof

Abstract

This application discloses a 5-glycosylated derivative of cycloicariin in the field of pharmaceutical technology, with the structural formula shown in formula (1), where R1 is H, C 1‑10 Alkyl, benzyl, propargyl, C 1‑6 The group consists of an alicyclic or aryl group; R2 is α-D-glucose or α-D-galactose. The 5-glycosylated derivative of cycloicin of this invention exhibits stronger anticancer activity and lower toxicity to normal cells. It can be used to prepare antitumor drugs and has broad application prospects.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to cycloicariin 5-glycosylated derivatives, their preparation methods, and uses. Background Technology

[0002] In recent years, the incidence and mortality rates of malignant tumors in my country have been rising year by year, becoming a major killer threatening the health of the Chinese people. The main treatments for cancer include surgery, radiotherapy, chemotherapy, and molecular targeted therapy, but existing treatments have many limitations. Firstly, cancer treatment faces two major challenges: a high metastasis rate and a high recurrence rate. 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 Chinese herbal medicines, more and more researchers are focusing on their anti-tumor efficacy. Research results show that they can kill tumor cells at multiple targets and have the advantages of relatively low cost and low toxicity.

[0003] Icaritin (ICT) is a flavonoid compound, a yellow solid at room temperature. Its chemical name is 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)-4H-chromen-4-one, and its structure is shown below. Its molecular formula is C1. 21 H 20 O6, with a molecular weight of 368.3799. Icariin is obtained by hydrolyzing icariin, the main active monomer of epimedium. Icariin can be obtained by enzymatic hydrolysis of icariin with β-glucosidase. This preparation method involves complete deglycosylation with a high yield, simple operation, convenient post-reaction processing, and easy purification.

[0004]

[0005] Epimedium

[0006] Epimedium is a traditional Chinese medicine, belonging to the genus Epimedium in the Berberidaceae family. It has a pungent and sweet taste and is warm in nature. Its dried leaves are used medicinally, primarily to treat impotence, seminal emission, kidney yang deficiency, rheumatic pain, weakness of muscles and bones, numbness, and contractures. Modern pharmacological studies have shown that the main active components of Epimedium extract include icariin, icariin derivatives, total flavonoid derivatives of Epimedium, as well as alkaloids, anthraquinones, lignans, phytosterols, anthocyanins, terpenoids, chlorogenic acid, essential fatty acids, trace elements, and other bioactive and nutrient components. It not only possesses functions such as dilating coronary arteries, inhibiting microorganisms, anti-aging, and promoting bone cell growth, but also exhibits various biological activities such as inhibiting tumors.

[0007] Studies have shown that epimedium, as an active flavonoid component of epimedium, has multiple effects such as anti-tumor, anti-liver fibrosis, anti-osteoporosis, improvement of prostate function, neuroprotection, immunosuppression, anti-inflammation, anti-oxidation, and estrogen receptor-like effects. Moreover, its anti-tumor activity has a broad spectrum and it has inhibitory effects on a variety of tumors.

[0008] Like many natural products, icariin has the disadvantages of poor water solubility and low bioavailability, which greatly limits its clinical application.

[0009] Numerous clinical studies have demonstrated that carbohydrates have many binding receptors on cell surfaces, exhibiting cell-targeting properties and good water solubility, making them excellent carriers for lead drugs. Glycosyl compound-modified formulations can effectively improve problems such as low bioavailability, poor solubility, poor pharmacological activity, and reduce toxic side effects in certain drugs. Currently, naturally derived icariin glycoside derivatives, icariin I and II, have the structures shown below. It has been reported that icariin exhibits stronger antitumor activity than its glycosyl ligands, such as anti-breast cancer activity; however, the water solubility of icariin is significantly reduced after deglycosylation, thus affecting its bioavailability in vivo.

[0010] Summary of the Invention

[0011] To address the shortcomings of existing technologies, this invention modifies the structure of epimedium to provide a novel 5-glycosylated derivative of cyclic epimedium for the prevention or treatment of tumors.

[0012] One objective of this invention is to provide a 5-glycosylated derivative of cycloicin, the structural formula of which is shown in formula (1).

[0013]

[0014] Equation (1),

[0015] In the above formula, R1 represents H and C. 1-10 Alkyl, benzyl, propargyl, C 1-6 Alicyclic or aryl group; R2 is α-D glucose or α-D galactose.

[0016] The second objective of this invention is a method for preparing 5-glycosylated derivatives of cycloicariin, comprising the following steps:

[0017] ,

[0018] Step a: Icariin was refluxed with formic acid to obtain cyclic icariin A, the structural formula of which is shown in (2):

[0019]

[0020] Equation (2),

[0021] Step b: Cycloic icariin A is dissolved in a specific solvent with a haloalkane R1X under the action of a specific base B1, and then etherified under specific conditions to obtain 3-OR1 cycloicariin B, the structure of which is shown in formula (3):

[0022]

[0023] Equation (3),

[0024] Step c: Dissolve 3-OR1 cycloicariin B in a specific solvent, and react with α-D-acetylated bromide under specific base B2 catalysis to obtain 3-OR1-5-peracetylated sugar C, the structural formula of which is shown in (4):

[0025]

[0026] Equation (4),

[0027] Step d: Dissolve 3-OR1-5-peracetylated sugar C in a specific solvent, add a specific base B3, and react under specific conditions to obtain 3-OR1-5-sugar compound D, whose structural formula is shown in (1):

[0028]

[0029] Equation (1),

[0030] Where: R1 represents H and C 1-10 Alkyl, benzyl, propargyl, C 1-6 Alicyclic or aryl group; R2 is α-D glucose or α-D galactose; R3 is α-D acetylglucose or α-D acetylglucose.

[0031] Furthermore, step e is included, in which 3-OR1-5-sugar compound D is dissolved in a specific solvent, a specific catalyst is added, and hydrogenation is catalytically carried out to obtain compound (2), the structural formula of which is shown in (5).

[0032] ,

[0033] Where R1 is H or benzyl, and R2 is α-D-glucose.

[0034] Furthermore, the specific base B1, specific base B2, and specific base B3 are each independently selected from sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or NaH. Specific base B1 is preferably sodium carbonate or potassium carbonate; specific base B2 is preferably NaH; and specific base B3 is preferably potassium carbonate.

[0035] Furthermore, the haloalkanes R1X in step b refer to fluorinated hydrocarbons, chlorinated hydrocarbons, bromine hydrocarbons, or iodinated hydrocarbons.

[0036] Furthermore, the specific solvents for steps b, c, and d are each independently selected from: acetonitrile, dichloromethane, chloroform, acetone, tetrahydrofuran, DMF, or DMSO. The specific solvent for step b is preferably acetone, the specific solvent for step c is preferably DMF or DMSO, and the specific solvent for step d is preferably methanol, ethanol, or water.

[0037] Furthermore, the specific conditions for the etherification reaction in step b are a temperature of 25°C to 120°C and a reaction time of 1 to 24 hours.

[0038] Furthermore, the specific conditions for step c are: -20℃ to 100℃, reaction time 1 to 48 hours.

[0039] Furthermore, the specific conditions for step d are: 0–120°C, reaction time 0.5–12 hours.

[0040] Furthermore, the specific solvent in step e refers to: acetonitrile, methanol, ethanol, isopropanol, water, tetrahydrofuran, ethyl acetate, DMF, or DMSO. Methanol or ethanol is preferred.

[0041] Furthermore, the specific catalyst in step e refers to any one of Pd / C (5%), Pd / C (10%), Pd / C (20%), PtO2, Pt / C (10%), Pt / C (20%), Pd(OH)2 / C (10%), or Pd(OH)2 / C (20%).

[0042] Furthermore, the specific conditions for step e are: stirring at 0–100°C for 0.5–12 hours.

[0043] The third objective of this invention is to provide the application of the 5-glycosylated derivative of cycloicariin (1) in the preparation of antitumor drugs.

[0044] Furthermore, the aforementioned antitumor drug is an anti-colon cancer or anti-lung cancer drug.

[0045] The present invention demonstrates through experiments that the 5-glycosylated derivative of cycloicin represented by formula (1) of the present invention can significantly inhibit the in vitro growth of two tumor cell lines, HCT-116 and A549, and its activity is stronger than that of its parent icariin, and its cytotoxic activity against normal cell LO2 is relatively low. Detailed Implementation

[0046] 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.

[0047] 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.

[0048] Example 1: Preparation of cycloicariin

[0049] 50 mg (0.136 mmol) of icariin was weighed into a round-bottom flask, and 4 mL of formic acid was added. The reaction flask was then refluxed in an 85 °C oil bath. The reaction solution became clear at this point. The reaction continued, and a yellow solid gradually precipitated from the solution. After 4 hours of reaction, thin-layer chromatography was performed using a 4:1 (v / v) petroleum ether-ethyl acetate developing solvent. The reaction was considered complete when the presence of icariin was not detected on the thin-layer chromatography plate. After the reaction was complete, the reaction flask was placed in a 4 °C refrigerator for 10 min, filtered, and dried to obtain a yellow powdery solid cycloicariin (intermediate A, 45 mg, 89.7%). Intermediate A (89.7%), yellow solid; Rf = 0.23 (PE : EA = 6:1). 1 H NMR (400 MHz, Chloroform- d )δ 11.47 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.70 (s,1H), 6.23 (s, 1H), 3.87 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 1.87 (t, J = 6.8 Hz, 2H), 1.37 (s, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 177.62, 161.25, 160.24,158.54, 155.17, 153.26, 136.46, 129.88, 123.20, 114.28, 104.82, 103.71,99.09, 75.19, 55.32, 28.16, 26.78, 26.71.

[0050] Example 2: Preparation of 3-OR1-cycloicariin

[0051] 50 mg (intermediate A, 0.136 mmol) of cycloicariin was weighed into a reaction flask and dissolved in 1 mL of acetone by stirring. Under argon protection, 22.5 mg (0.163 mmol) of potassium carbonate and 1 equiv. of bromoalkane were added. The mixture was stirred at 28 °C and reacted for 10 min until the solution became clear. After 2.5 h of reaction, the reaction was analyzed by thin-layer chromatography with a 3:1 volume ratio of petroleum ether to ethyl acetate as the developing solvent. The absence of cycloicariin on the thin-layer chromatography plate indicated the completion of the reaction. After the reaction was complete, the solvent was removed under reduced pressure. The remaining solid product was extracted with distilled water and dichloromethane. The organic phase was dried, filtered, and then dried to obtain a yellow powdery solid 3-OR1 cycloicariin (intermediate B, 74%-92.3%).

[0052] Example 3: 3-OR1-5-holacylglycoside cycloicariin (intermediate C)

[0053] Weigh 100 mg of intermediate B into a reaction flask, add 1 mL of N,N-dimethylamine and stir to dissolve. Under ice bath conditions and argon protection, add 1.3 equiv. 60% sodium hydride and stir for 0.5 hours. Then add 1.2 equiv. α-D-acetyl bromide glucose or α-D-acetyl bromide galactose and stir at 0℃-28℃. After 10 min of reaction, the reaction solution changes from yellow to brown. After 15 hours of reaction, the reaction is confirmed by thin-layer chromatography with a 2:1 volume ratio of petroleum ether to ethyl acetate as the developing solvent. The absence of intermediate B on the thin-layer chromatography plate indicates the completion of the reaction. After the reaction is complete, extract with distilled water and dichloromethane, dry the organic phase, filter, and purify by rapid column chromatography. Dry to obtain a white powdery solid intermediate C (52%-64%).

[0054] Example 4: 3-OR1-5-glycocyclic icariin

[0055] Weigh 50 mg of intermediate C into a round-bottom flask, add 2 mL of anhydrous methanol and 8 equiv. potassium carbonate, and stir at 28 °C. After 5 min of reaction, the reaction solution becomes clear. After 1 hour of reaction, the reaction is detected by thin-layer chromatography with a volume ratio of 20:1 dichloromethane-methanol as the developing solvent. The absence of intermediate E on the thin-layer chromatography plate indicates the completion of the reaction. After the reaction is complete, the solvent is removed under reduced pressure, and the mixture is extracted with distilled water and dichloromethane. The organic phase is dried, filtered, and dried to obtain a yellow powdery solid compound (2) (85%-92%), which is the compound shown in formula (2).

[0056]

[0057] Equation (2)

[0058] Example 5:

[0059] Compound (2) (where R1 is benzyl and R2 is α-D-glucose) (50 mg, 0.087 mmol) was weighed and dissolved in 2 mL of anhydrous methanol. 10% Mw catalyst Pd / C was added, and the mixture was stirred at 28 °C under hydrogen atmosphere. After 2.5 hours of reaction, the reaction was detected by thin-layer chromatography with a 20:1 volume ratio of dichloromethane to methanol as the developing solvent. The absence of reactant (2) on the thin-layer chromatography plate indicated the completion of the reaction. After the reaction was complete, the mixture was filtered while hot, the solvent was removed from the filtrate under reduced pressure, and the residue was dried to obtain a yellow powdery solid compound (2). ’ (where R1 is H and R2 is α-D-glucose), its structural formula is shown in (6).

[0060]

[0061] Equation (6)

[0062] Data on synthesized compounds

[0063]

[0064] Intermediate B (R1 = Bn, 92.3%), yellow solid, Mp 210.5-227.1℃. Rf = 0.75 (PE : EA = 6:1). 1 H NMR (400 MHz, Chloroform- d ) δ 12.46 (s, 1H), 8.04 (d, J = 8.9 Hz, 2H),7.41 – 7.36 (m, 2H), 7.33 – 7.27 (m, 3H), 6.97 (d, J = 8.9 Hz, 2H), 6.26 (s,1H), 5.08 (s, 2H), 3.89 (s, 3H), 2.85 (t, J = 6.8 Hz, 2H), 1.88 (d, J = 6.8 Hz, 2H), 1.38 (s, 6H). 13 C NMR (101 MHz, Chloroform- d) δ 178.78, 161.44, 160.01,159.46, 155.78, 153.79, 137.41, 136.54, 130.22, 128.73, 128.27, 128.16,123.23, 113.84, 105.68, 99.93, 99.51, 74.13, 55.40, 31.69, 26.61, 16.26.

[0065] Compound B1, R1 = methyl, (91.9%), yellow solid, Mp 231.5-239.1℃. Rf = 0.35 (PE :EA = 6 : 1).

[0066] Compound B2, R1 = butyl, (84.7%), yellow solid, Mp 220.5-237.1℃. Rf = 0.68 (PE :EA = 6 : 1).

[0067] Compound B3, R1=heptyl, (84.8%), yellow solid, Mp 199.7-215.1℃. Rf = 0.72 (PE :EA = 6 : 1).

[0068] Compound B4, R1 = octyl, (89.6%), yellow solid, Mp 200.4-209.3℃. Rf = 0.69 (PE :EA = 6 : 1).

[0069] Compound B5, R1 = nonyl, (86.5%), yellow solid; Mp 234.3-242.5℃. Rf = 0.70 (PE :EA = 6 : 1).

[0070] Compound B6, R1=decyl, (94.7%), yellow solid, Mp 231.3-239.6℃. Rf = 0.64 (PE :EA = 6 : 1).

[0071] Compound B7, R1 = cyclopentyl, (79.7%), yellow solid, Mp 221.6-227.8℃. Rf = 0.69 (PE: EA = 6:1).

[0072] Compound B8, R1 = cyclohexyl, (74%), yellow solid, Mp 207.8-219.4℃. Rf = 0.68 (PE :EA = 6 : 1).

[0073] Compound B9, R1=propynyl, (78.5%), yellow solid, Mp 199.4-204.9℃. Rf = 0.64 (PE: EA = 6:1).

[0074]

[0075] Compound C1 (63.1%), white solid; Mp 240.5-247.1℃. Rf = 0.16 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.04 (d, J = 8.7 Hz, 2H), 6.97 (d, J = 8.7Hz, 2H), 6.59 (s, 1H), 5.43 (t, J = 8.7 Hz, 1H), 5.29 (t, J = 8.9 Hz, 1H), 5.14 –5.06 (m, 2H), 4.25 – 4.17 (m, 2H), 3.89 (dt, J = 6.8, 2.9 Hz, 1H), 3.85 (s,3H), 3.79 (s, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.12 (d, J = 5.7 Hz, 6H), 2.02 (d, J =1.4 Hz, 6H), 1.85 (t, J = 6.7 Hz, 2H), 1.33 (d, J = 7.0 Hz, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 178.84, 165.34, 162.48, 160.16, 158.70, 157.72, 142.76,140.70, 133.44, 132.28, 131.81, 131.70, 126.33, 117.31, 112.84, 108.21,107.85, 107.76, 81.07, 80.03, 79.67, 77.15, 73.62, 65.01, 58.43, 34.93,29.47, 20.09.

[0076]

[0077] Compound C2 (55.3%), white solid; Mp 120.5-131.1℃. Rf = 0.54 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.06 – 8.01 (m, 2H), 6.98 – 6.92 (m, 2H), 6.60 (d, J = 2.0 Hz, 1H), 5.41 (dd, J = 9.6, 7.9 Hz, 1H), 5.28 (t, J = 9.4 Hz, 1H),5.14 – 5.03 (m, 3H), 4.19 (t, J = 4.6 Hz, 2H), 4.09 – 4.01 (m, 2H), 3.83 (s,3H), 2.85 (t, J = 6.7 Hz, 2H), 2.12 (s, 2H), 2.11 (s, 2H), 2.08 (d, J = 0.9 Hz, 1H), 2.06 (d, J = 2.1 Hz, 1H), 2.05 (s, 1H), 2.02 (s, 1H), 2.00 (s, 2H), 2.00(d, J = 1.2 Hz, 3H), 1.98 (d, J = 1.7 Hz, 1H), 1.83 (t, J = 6.8 Hz, 2H), 1.64 (p, J =6.8 Hz, 2H), 1.32 (d, J = 7.5 Hz, 6H), 1.19 (d, J = 7.3 Hz, 8H), 0.82 (t, J = 6.8Hz, 3H). 13 C NMR (101 MHz, Chloroform- d) δ 173.20, 170.71, 170.33, 169.94,169.39, 160.90, 157.52, 155.53, 155.02, 152.18, 140.06, 129.76, 123.70,113.72, 109.88, 104.35, 103.79, 100.52, 91.60, 72.70, 72.68, 72.62, 72.33,72.01, 70.57, 70.10, 68.66, 67.61, 62.28, 61.35, 61.29, 55.31, 31.75, 31.69, 30.10, 29.36, 29.24, 26.73, 26.41, 25.95, 22.62, 20.97, 20.81, 20.74, 20.70, 20.66, 20.63, 20.55, 16.74, 14.09.

[0078]

[0079] Compound C3 (52.5%), white solid; Mp 264.6-272.5℃. Rf = 0.35 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.04 – 7.98 (m, 2H), 7.44 – 7.39 (m, 2H), 7.33 – 7.25 (m, 3H), 6.96 – 6.90 (m, 2H), 6.65 (d, J = 1.4 Hz, 1H), 5.48 (dd, J =9.5, 8.0 Hz, 1H), 5.32 (d, J = 9.2 Hz, 1H), 5.17 – 5.07 (m, 3H), 4.87 (d, J =10.5 Hz, 1H), 4.27 – 4.18 (m, 2H), 3.90 (td, J = 6.4, 3.2 Hz, 1H), 3.85 (d, J =1.4 Hz, 3H), 2.87 (t, J = 6.8 Hz, 2H), 2.14 (dd, J = 9.3, 1.4 Hz, 6H), 2.04 (dd, J= 5.3, 1.4 Hz, 6H), 1.86 (d, J = 6.7 Hz, 2H), 1.34 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.15, 170.74, 170.36, 169.99, 169.53, 160.99,157.68, 155.69, 155.08, 152.74, 139.50, 137.06, 129.89, 128.89, 128.20,128.00, 123.55, 113.74, 109.84, 104.36, 103.65, 100.61, 73.67, 72.71, 72.09,70.57, 68.69, 62.31, 55.37, 31.71, 26.75, 26.45, 21.04, 20.77, 20.68, 20.65, 16.75.

[0080]

[0081] Compound C4 (52.4%), white solid; Mp 165.5-171.2℃. Rf = 0.25 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.09 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0Hz, 2H), 6.62 (s, 1H), 5.47 – 5.42 (m, 1H), 5.32 – 5.27 (m, 1H), 5.15 – 5.11(m, 1H), 5.11 – 5.05 (m, 2H), 4.26 (dt, J = 6.0, 2.7 Hz, 1H), 4.21 (t, J = 4.2Hz, 2H), 3.86 (s, 3H), 2.87 (t, J = 6.6 Hz, 2H), 2.14 (d, J = 2.8 Hz, 3H), 2.03(d, J = 4.7 Hz, 6H), 2.00 (d, J= 4.5 Hz, 3H), 1.86 (d, J = 6.9 Hz, 2H), 1.60 –1.50 (m, 2H), 1.47 – 1.40 (m, 2H), 1.34 (d, J = 7.4 Hz, 6H), 1.19 – 1.13 (m, 2H), 1.11 – 1.04 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.48, 170.74,170.35, 170.00, 169.52, 160.76, 157.45, 155.55, 155.02, 152.67, 138.57,130.16, 124.11, 113.50, 104.36, 103.92, 100.62, 75.90, 72.69, 72.02, 70.61,69.75, 68.67, 62.29, 55.32, 32.81, 32.34, 31.74, 26.79, 26.39, 25.46, 24.25, 24.10, 21.00, 20.77, 20.68, 20.65, 16.76.

[0082]

[0083] Compound C5 (61.1%), white solid; Mp 129.7-135.1℃. Rf = 0.26 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.09 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 9.0Hz, 2H), 6.60 (s, 1H), 5.42 (dd, J = 9.6, 7.9 Hz, 1H), 5.29 (t, J = 9.4 Hz, 1H), 5.12 (d, J = 9.7 Hz, 1H), 5.07 (d, J = 7.9 Hz, 1H), 4.96 (dd, J = 15.7, 2.5 Hz, 1H), 4.83 (dd, J= 15.7, 2.5 Hz, 1H), 4.21 (dd, J = 6.3, 4.5 Hz, 2H), 3.89 (dt, J =6.9, 3.0 Hz, 1H), 3.85 (s, 3H), 2.87 (t, J = 6.7 Hz, 2H), 2.29 (t, J = 2.5 Hz,1H), 2.13 (s, 3H), 2.10 (s, 3H), 2.05 (dd, J = 6.2, 2.4 Hz, 1H), 2.02 (d, J = 4.9Hz, 6H), 2.00 – 1.97 (m, 1H), 1.85 (t, J = 6.7 Hz, 2H), 1.33 (d, J = 7.2 Hz, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.98, 170.70, 170.33, 169.83, 169.50,161.10, 157.80, 155.57, 155.07, 153.20, 138.03, 130.06, 123.43, 113.74,109.51, 104.30, 103.45, 100.37, 76.04, 75.78, 72.67, 72.09, 70.58, 68.63,62.26, 58.86, 55.34, 31.68, 26.71, 26.46, 20.93, 20.74, 20.66, 20.63, 16.74.

[0084]

[0085] Compound C6 (63.4%), white solid; Mp 240.5-247.1℃. Rf = 0.06 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.04 (dd, J = 9.0, 2.1 Hz, 2H), 6.98 (dd, J=9.0, 2.0 Hz, 2H), 6.61 (s, 1H), 5.73 – 5.66 (m, 1H), 5.43 (q, J = 4.5, 3.1 Hz,2H), 5.10 – 5.03 (m, 2H), 4.21 – 4.17 (m, 1H), 4.06 (dd, J = 7.2, 5.2 Hz, 1H), 3.85 (d, J = 2.1 Hz, 3H), 3.80 (d, J = 1.9 Hz, 3H), 2.93 (d, J = 2.2 Hz, 1H), 2.85(d, J = 2.1 Hz, 1H), 2.14 (d, J = 2.0 Hz, 3H), 2.11 (dd, J = 4.9, 2.4 Hz, 6H), 2.00(d, J = 5.3 Hz, 3H), 1.96 (d, J = 2.3 Hz, 1H), 1.86 (d, J = 7.1 Hz, 1H), 1.33 (s, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.26, 170.58, 170.33, 170.30, 169.92,161.03, 157.70, 155.56, 155.07, 152.09, 140.87, 129.61, 123.47, 113.94,109.69, 104.09, 103.25, 100.74, 90.56, 71.18, 70.99, 68.35, 68.23, 67.87,67.10, 61.81, 59.79, 55.36, 31.71, 26.61, 26.53, 21.03, 20.69, 20.64, 16.74.

[0086]

[0087] Compound C7 (55.3%), white solid; Mp 196.5–210.3 °C. Rf = 0.19 (PE: EA = 2:1). 1 H NMR (400 MHz, Chloroform-d ) δ 8.08 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9Hz, 2H), 6.61 (s, 1H), 5.73 (dd, J = 10.3, 8.1 Hz, 1H), 5.61 (d, J = 7.9 Hz, 1H),5.44 (d, J = 3.3 Hz, 1H), 5.39 – 5.36 (m, 1H), 5.33 (d, J = 3.3 Hz, 1H), 5.08 –4.99 (m, 3H), 4.23 – 4.16 (m, 2H), 4.10 – 4.07 (m, 1H), 3.86 (s, 3H), 3.79(d, J = 8.2 Hz, 2H), 2.87 (d, J = 6.2 Hz, 2H), 2.14 (s, 3H), 2.12 (s, 3H), 2.09(d, J = 2.8 Hz, 3H), 1.98 (d, J = 10.3 Hz, 6H), 1.89 (s, 3H), 1.85 (t, J = 6.7 Hz,2H), 1.35 (s, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.33, 170.60, 170.33,170.04, 160.92, 157.58, 155.58, 155.06, 152.24, 140.06, 129.74, 123.71,113.75, 109.78, 104.14, 103.50, 100.89, 90.59, 72.03, 71.14, 70.99, 68.18,67.90, 67.09, 61.81, 55.35, 32.11, 31.72, 26.65, 26.50, 21.05, 20.70, 20.65,19.09, 16.74, 13.86.

[0088]

[0089] Compound C8 (62.4%), white solid; M.p. 145.9 - 155.7 °C. Rf = 0.55 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.06 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.9Hz, 2H), 6.64 (s, 1H), 5.71 (dd, J = 10.5, 8.0 Hz, 1H), 5.44 (d, J = 3.4 Hz, 1H),5.08 (dd, J = 10.4, 3.4 Hz, 1H), 5.03 (d, J = 7.7 Hz, 1H), 4.18 (td, J = 11.2,10.7, 6.5 Hz, 2H), 4.12 – 4.04 (m, 2H), 3.86 (d, J = 1.1 Hz, 3H), 3.84 – 3.80(m, 1H), 2.87 (t, J = 6.8 Hz, 2H), 2.14 (d, J = 3.0 Hz, 6H), 2.12 – 2.08 (m, 3H),2.00 (s, 3H), 1.84 (d, J = 6.9 Hz, 2H), 1.65 (q, J = 7.0, 6.5 Hz, 2H), 1.33 (d, J =5.2 Hz, 6H), 1.32 – 1.27 (m, 2H), 1.26 – 1.18 (m, 6H), 0.84 (t, J = 6.4 Hz,3H). 13 C NMR (101 MHz, Chloroform- d) δ 173.27, 170.60, 170.33, 170.32, 170.02,160.89, 157.54, 155.60, 155.04, 152.18, 140.06, 129.77, 123.72, 113.72,109.82, 104.16, 103.59, 100.95, 72.36, 71.13, 70.99, 67.86, 67.10, 61.83,55.33, 31.81, 31.71, 30.11, 29.08, 26.66, 26.50, 25.92, 22.57, 21.09, 20.72, 20.67, 16.75, 14.11.

[0090]

[0091] Compound C9 (53.2%), white solid; Mp 129.4–35.1 °C. Rf = 0.43 (PE:EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.08 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz,2H), 6.61 (s, 1H), 5.74 (ddd, J = 10.0, 8.2, 1.8 Hz, 1H), 5.62 (d, J = 7.9 Hz, 1H), 5.44 (d, J = 3.2 Hz, 1H), 5.40 – 5.35 (m, 1H), 5.34 (d, J = 3.3 Hz, 1H),5.08 – 4.98 (m, 3H), 4.25 – 4.17 (m, 2H), 4.10 – 4.06 (m, 1H), 3.86 (s, 3H),3.82 (s, 1H), 3.79 – 3.75 (m, 1H), 2.88 (t, J = 6.4 Hz, 2H), 2.13 (dd, J = 9.4,4.8 Hz, 12H), 2.09 (s, 3H), 2.00 (s, 3H), 1.98 (s, 3H), 1.90 (s, 3H), 1.71(d, J= 6.3 Hz, 3H), 1.34 (d, J = 8.3 Hz, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ172.36, 170.59, 170.33, 170.28, 170.11, 169.99, 169.82, 161.10, 157.90,155.99, 155.07, 154.13, 135.37, 130.43, 123.38, 113.36, 109.36, 104.10,102.89, 101.02, 98.82, 71.22, 70.97, 70.87, 70.22, 69.22, 67.80, 67.04,66.83, 61.83, 60.54, 55.33, 31.67, 26.79, 26.42, 21.04, 21.02, 20.73, 20.67, 20.63, 20.60, 16.72.

[0092]

[0093] Compound C10 (49.7%), white solid; Mp 121.5-137.2 ℃. Rf = 0.17 (PE : EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.07 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.6Hz, 2H), 6.61 (s, 1H), 5.78 – 5.70 (m, 1H), 5.61 (d, J = 7.9 Hz, 1H), 5.44 (d, J = 3.2 Hz, 1H), 5.37 (d, J = 10.3 Hz, 1H), 5.33 (d, J = 3.7 Hz, 1H), 5.09 – 4.97(m, 3H), 4.25 – 4.15 (m, 2H), 4.08 (d, J = 6.4 Hz, 1H), 3.85 (s, 3H), 3.81 (d, J = 6.9 Hz, 2H), 3.78 (d, J= 3.1 Hz, 1H), 3.75 (d, J = 4.3 Hz, 1H), 2.87 (t, J = 6.6Hz, 2H), 2.12 (dd, J = 9.5, 4.7 Hz, 12H), 2.08 (d, J = 1.8 Hz, 3H), 1.98 (d, J =10.3 Hz, 6H), 1.89 (s, 3H), 1.85 (t, J = 6.7 Hz, 3H), 1.34 (d, J = 8.3 Hz, 6H). 13 CNMR (101 MHz, Chloroform- d ) δ 170.60, 170.34, 170.29, 170.12, 170.00, 169.85,161.10, 157.91, 155.96, 155.08, 154.13, 135.36, 130.42, 123.36, 113.37,109.34, 104.09, 102.85, 100.97, 98.79, 71.22, 70.97, 70.87, 70.22, 69.22,67.82, 67.04, 66.84, 61.83, 60.54, 55.33, 31.67, 26.78, 26.42, 21.04, 21.02, 20.72, 20.68, 20.66, 20.63, 20.59, 16.71.

[0094]

[0095] Compound C11 (56.2%), white solid; Mp 294.3-299.2℃. Rf = 0.16 (PE: EA = 2:1). 1 H NMR (400 MHz, Chloroform- d ) δ 8.01 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 6.3Hz, 2H), 7.28 (d, J = 7.5 Hz, 3H), 6.93 (d, J = 8.9 Hz, 2H), 6.67 (s, 1H), 5.75(dd,J = 10.5, 8.1 Hz, 1H), 5.46 (d, J = 3.4 Hz, 1H), 5.14 (d, J = 10.6 Hz, 1H), 5.10 (dd, J = 10.5, 3.3 Hz, 1H), 5.05 (d, J = 7.9 Hz, 1H), 4.87 (d, J = 10.6 Hz,1H), 4.27 – 4.17 (m, 2H), 4.10 – 4.06 (m, 1H), 3.85 (s, 3H), 2.87 (t, J = 6.3Hz, 2H), 2.13 (s, 6H), 2.01 (d, J = 6.9 Hz, 6H), 1.85 (t, J = 6.8 Hz, 2H), 1.35(d, J = 4.4 Hz, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.23, 170.61, 170.35,170.32, 170.06, 160.99, 157.71, 155.74, 155.10, 152.76, 139.50, 137.06,129.89, 128.94, 128.19, 128.00, 123.54, 113.73, 109.76, 104.17, 103.45,101.02, 90.58, 73.73, 71.20, 71.01, 67.89, 67.12, 61.85, 55.36, 31.70, 29.67, 26.65, 26.53, 21.12, 20.71, 20.65, 16.73.

[0096]

[0097] Compound L1 (83.1%), yellow solid; Mp 150.4-168.4℃. Rf = 0.29 (DCM: MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 7.81 (d, J= 8.6 Hz, 1H), 7.33 – 7.27 (m, 1H),7.24 (dd, J = 6.6, 3.3 Hz, 3H), 6.75 (d, J = 8.6 Hz, 2H), 6.61 (s, 1H), 4.86 –4.78 (m, 3H), 4.68 (d, J = 6.2 Hz, 1H), 3.91 (dd, J = 12.3, 2.1 Hz, 1H), 3.81 –3.74 (m, 1H), 3.70 (s, 3H), 3.49 – 3.42 (m, 2H), 3.39 (dd, J = 12.6, 6.4 Hz,1H), 3.29 (d, J = 1.5 Hz, 1H), 2.71 (dd, J = 15.2, 7.4 Hz, 2H), 1.75 (t, J = 6.7Hz, 2H), 1.29 (d, J = 4.5 Hz, 5H). 13 C NMR (101 MHz, DMSO- d 6) δ 178.84 (s),165.34 (s), 162.48 (s), 160.16 (s), 158.70 (s), 157.72 (s), 142.76 (s),140.70 (s), 133.44 (s), 132.28 (s), 131.76 (d, J = 10.4 Hz), 126.33 (s), 117.31(s), 112.84 (s), 108.21 (s), 107.81 (d, J = 9.1 Hz), 81.07 (s), 80.03 (s),79.67 (s), 77.13 (d, J = 3.6 Hz), 73.62 (s), 65.01 (s), 58.43 (s), 34.93 (s),29.47 (s), 20.09 (s).

[0098]

[0099] Compound L2 (81.1%), yellow solid; Mp 222.0-238.5℃. Rf = 0.16 (DCM: MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.04 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.72 (s, 1H), 4.79 (d, J = 7.5 Hz, 3H), 4.64 (s, 2H), 3.92 (d, J = 12.0 Hz, 1H),3.84 (s, 2H), 3.75 (s, 3H), 3.60 – 3.46 (m, 2H), 3.44 (t, J = 7.1 Hz, 3H), 2.96– 2.84 (m, 2H), 1.91 (t, J = 7.1 Hz, 2H), 1.37 (d, J = 6.6 Hz, 5H). 13 C NMR (101MHz, DMSO- d 6) δ 175.04 (s), 161.65 (s), 158.72 (s), 156.30 (s), 154.92 (s), 153.64 (s), 140.35 (s), 129.59 (s), 122.44 (s), 113.68 (d, J = 5.6 Hz), 108.85(s), 104.33 (s), 103.94 (d, J = 12.0 Hz), 77.14 (s,), 76.16 (s), 75.76 (s),73.33 (s), 69.73 (s), 61.08 (s), 58.81 (s), 54.50 (s), 31.06 (s), 25.46 (d, J =1.9 Hz), 16.19 (s).

[0100]

[0101] Compound L3 (87.8%), yellow solid; Mp 120.4-147.6℃. Rf = 0.17 (DCM: MeOH = 20:1). 11H NMR (400 MHz, DMSO- d 6) δ 8.01 (s, 1H), 6.90 (s, 1H), 6.63 (s, 1H), 4.74(d, J = 29.4 Hz, 1H), 3.91 (d, J = 12.2 Hz, 1H), 3.77 (s, 1H), 3.46 (s, 1H), 2.80(s, 1H), 1.87 (s, 1H), 1.37 (s, 1H). 13 13C NMR (101 MHz, DMSO- d 6) δ 173.80 (s),161.57 (s), 156.66 (s), 154.88 (s), 153.92 (s), 137.68 (s), 130.44 (s),122.93 (s), 114.51 (s), 108.98 (s), 104.67 (s), 104.30 (s), 79.63 (s), 79.29(s), 77.96 (s), 76.95 (s), 75.98 (s), 74.02 (s), 70.18 (s), 61.32 (s), 58.76(s), 55.83 (s).

[0102]

[0103] Compound L4 (92.4%), yellow solid; M.p. 210.2 - 235.8 °C. Rf = 0.30 (DCM:MeOH = 20:1). 1 1H NMR (400 MHz, DMSO- d 6) δ 8.08 (dd, J = 8.5, 3.5 Hz, 1H), 7.08 (t, J = 6.0Hz, 1H), 6.64 (d, J = 3.3 Hz, 1H), 4.72 (dd, J = 7.2, 3.4 Hz, 1H), 4.21 – 4.14(m, 1H), 3.81 (d, J = 3.2 Hz, 1H), 3.69 (d, J = 11.4 Hz, 1H), 3.48 (d, J= 6.2 Hz,3H), 3.32 – 3.26 (m, 1H), 3.16 – 3.11 (m, 1H), 2.88 – 2.81 (m, 1H), 1.83 (t, J = 6.4 Hz, 1H), 1.70 (s, 1H), 1.58 (s, 1H), 1.39 – 1.35 (m, 1H), 1.31 (d, J =5.4 Hz, 1H), 1.13 (dd, J = 25.4, 12.9 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ174.40 – 174.20 (m), 161.29 (s), 158.23 (s), 156.70 (s), 155.04 – 154.84 (m), 138.06 (s), 130.57 (s), 123.51 (s), 114.33 (s), 109.18 (s), 104.55 (d, J = 7.7Hz), 103.94 (s), 79.28 (s), 78.06 (s), 76.83 (s), 75.94 (s), 74.01 (s), 70.16(s), 61.29 (s), 55.78 (s), 26.71 (s).

[0104]

[0105] Compound L5 (85.5%), yellow solid; Mp 76.7–108.6 °C. Rf = 0.27 (DCM: MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.00 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.64 (s, 1H), 4.71 (d, J = 7.2 Hz, 1H), 4.05 – 3.76 (m, 5H), 3.79 (d, J= 7.9 Hz,3H), 3.80 – 3.53 (m, 5H), 6.02 – 2.12 (m, 63H), 5.23 – 2.12 (m, 58H), 3.53 –3.24 (m, 32H), 3.09 (dd, J = 43.7, 34.9 Hz, 3H), 2.83 (t, J = 6.5 Hz, 3H), 2.49(d, J = 15.7 Hz, 2H), 1.82 (t, J = 6.5 Hz, 3H), 1.63 – 1.49 (m, 3H), 1.28 (d, J =17.6 Hz, 6H), 1.26 – 1.04 (m, 11H), 1.04 – 0.92 (m, 1H), 0.90 – 0.72 (m, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 174.05 (s), 161.42 (s), 158.29 (s), 156.68 (s),154.91 (s), 153.34 (s), 139.61 (s), 130.24 (s), 123.10 (s), 114.46 (s),109.31 (s), 104.62 (d, J = 12.5 Hz), 104.11 (s), 78.00 (s), 76.85 (s), 75.94(s), 74.00 (s), 71.99 (s), 70.17 (s), 61.31 (s), 55.78 (s), 40.47 (s), 40.18(d, J = 15.6 Hz), 40.05 (s), 39.84 (s), 39.63 (s), 39.42 (s), 39.21 (s), 31.63(s), 31.33 (s), 29.85 (s), 29.10 (d, J = 3.9 Hz), 26.65 (d, J = 10.1 Hz), 25.88(s), 22.52 (s), 16.53 (s), 14.37 (s).

[0106]

[0107] Compound L6 (88.4%), yellow solid; Mp 224.8-233.5℃. Rf = 0.12 (DCM : MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.02 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz,2H), 6.64 (s, 1H), 5.39 (s, 1H), 4.95 (s, 1H), 4.78 (d, J = 4.2 Hz, 1H), 4.66(d, J = 7.7 Hz, 1H), 4.64 – 4.58 (m, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 3.69 –3.63 (m, 2H), 2.92 – 2.81 (m, 2H), 1.91 – 1.79 (m, 2H), 1.30(d, J = 4.5 Hz, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 161.50, 158.33, 153.01, 140.56, 130.10,122.98, 114.72, 109.36, 104.63, 76.85, 76.59, 72.88, 71.15, 61.09, 59.81,55.83, 26.71, 26.61.

[0108]

[0109] Compound L7 (91.4%), yellow solid; Mp 294.3-301.5 ℃. Rf = 0.31 (DCM : MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 7.99 (d, J = 8.5 Hz, 2H), 7.31 (dt, J = 22.8, 8.0 Hz, 5H), 7.03 (d, J = 8.5 Hz, 2H), 6.64 (s, 1H), 5.50 (s, 1H), 5.00 (d, J=11.1 Hz, 2H), 4.92 (s, 1H), 4.69 (d, J = 7.7 Hz, 1H), 3.79 (s, 3H), 3.67 (s,2H), 3.57 (d, J = 11.2 Hz, 2H), 2.82 (t, J = 6.8 Hz, 2H), 1.82 (t, J = 7.0 Hz, 2H), 1.31 (s, 6H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.97, 161.45, 158.34, 154.92,153.53, 139.08, 137.19, 130.26, 128.76, 128.68, 128.49, 122.96, 114.50,109.30, 105.19, 104.52, 103.90, 76.85, 76.58, 73.26, 72.94, 71.17, 68.47,60.93, 55.82, 31.32, 26.73, 26.60, 16.53.

[0110]

[0111] Compound L8 (87.3%), yellow solid; Mp 140.1-145.8 ℃. Rf = 0.28 (DCM : MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.06 – 8.01 (m, 2H), 7.12 – 7.07 (m, 2H), 6.64 (s, 1H), 5.41 (d, J = 2.0 Hz, 1H), 4.92 (d, J = 5.9 Hz, 1H), 4.76 (t, J = 5.3Hz, 1H), 4.65 (d, J = 7.7 Hz, 1H), 4.58 (d, J = 4.5 Hz, 1H), 3.95 – 3.89 (m, 1H), 3.84 (d, J= 6.6 Hz, 1H), 3.81 (s, 3H), 3.66 – 3.62 (m, 2H), 3.57 – 3.55 (m,2H), 2.85 (t, J = 6.9 Hz, 2H), 1.83 (t, J = 6.7 Hz, 2H), 1.58 (dt, J = 14.3, 6.7Hz, 2H), 1.31 (d, J = 5.0 Hz, 6H), 1.18 (s, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 174.03, 161.45, 156.87, 154.94, 153.25, 130.22, 123.13,114.58, 105.23, 76.85, 60.95, 55.84, 55.36, 31.95, 26.72, 26.60, 19.05,14.11.

[0112]

[0113] Compound L9 (85.7%), yellow solid; Mp 245.1-254.13℃. Rf = 0.41 (DCM : MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.00 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz,2H), 6.64 (s, 1H), 5.41 (s, 1H), 4.86 (d, J = 60.0 Hz, 2H), 4.64 (s, 1H), 3.90(s, 1H), 3.80 (s, 3H), 3.65 (s, 2H), 3.57 (s, 2H), 2.83 (s, 2H), 2.47 (s,1H), 1.82 (s, 2H), 1.55 (s, 2H), 1.23 (d, J = 60.6 Hz, 14H), 0.79 (s, 3H). 13 CNMR (101 MHz, DMSO- d6) δ 174.04, 158.27, 156.91, 154.91, 153.30, 139.63,130.22, 123.11, 114.46, 109.37, 105.47, 104.10, 76.81, 76.60, 72.87, 71.97,71.15, 68.63, 61.06, 55.78, 31.67, 29.88, 28.85, 26.71, 26.59, 25.85, 22.46,14.37.

[0114]

[0115] Compound L10 (89.6%), yellow solid; Mp 145.8-156.3 ℃. Rf = 0.37 (DCM : MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.02 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 8.7 Hz,2H), 6.62 (s, 1H), 5.43 (s, 1H), 4.98 (s, 3H), 4.65 (d, J = 7.7 Hz, 1H), 3.95 –3.89 (m, 1H), 3.86 – 3.82 (m, 1H), 3.81 (s, 3H), 3.79 (s, 1H), 3.69 – 3.63(m, 2H), 3.57 (q, J = 4.7, 4.0 Hz, 2H), 3.55 – 3.51 (m, 1H), 2.83 (d, J = 7.1 Hz, 2H), 1.83 (t, J = 6.7 Hz, 2H), 1.58 – 1.53 (m, 2H), 1.31 (d, J = 5.0 Hz, 6H),1.24 – 1.14 (m, 12H), 0.81 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO- d6) δ173.98, 161.41, 158.25, 156.89, 154.93, 153.25, 139.63, 130.24, 123.15,114.47, 109.34, 105.27, 104.52, 76.80, 76.60, 72.97, 72.00, 71.17, 68.48,60.93, 55.78, 31.72, 29.87, 29.39, 29.18, 29.07, 26.71, 26.60, 25.89, 22.52,14.40.

[0116]

[0117] Compound L11 (89.3%), yellow solid; Mp 185.2–196.1 °C. Rf = 0.38 (DCM : MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.02 – 7.96 (m, 2H), 7.08 – 7.01 (m, 2H), 6.63 (s, 1H), 5.42 (d, J = 2.0 Hz, 1H), 4.99 – 4.89 (m, 1H), 4.79 (t, J = 5.2 Hz, 1H), 4.63 (dd, J = 9.9, 6.2 Hz, 2H), 3.90 (dt, J = 9.6, 6.4 Hz, 1H), 3.79 (s,3H), 3.68 – 3.63 (m, 2H), 3.57 (d, J = 4.3 Hz, 3H), 2.81 (d, J = 7.3 Hz, 2H), 1.82 (t, J = 6.8 Hz, 2H), 1.54 (p, J = 6.6 Hz, 2H), 1.30 (d, J = 5.5 Hz, 6H), 1.21(d, J = 7.1 Hz, 2H), 1.16 – 1.15 (m, 3H), 1.13 (s, 7H), 0.79 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6) δ 174.05, 161.41, 158.27, 156.89, 154.90, 153.28,130.21, 123.08, 114.42, 109.34, 105.42, 104.59, 104.05, 101.63, 76.81, 76.57,74.50, 72.85, 72.37, 71.96, 71.19, 71.12, 68.60, 64.82, 63.20, 61.02, 55.76,31.73, 31.31, 29.86, 29.45, 29.39, 29.19, 29.17, 26.70, 26.56, 25.90, 22.55, 16.53, 14.39.

[0118]

[0119] Compound L12 (87.1%), yellow solid; Mp 165.7-195.2℃. Rf = 0.12 (DCM: MeOH = 20:1). 1 H NMR (400 MHz, DMSO- d 6) δ 8.15 – 8.06 (m, 1H), 7.97 (s, 1H), 6.97 – 6.75 (m, 1H), 6.67 – 6.56 (m, 1H), 4.73 (s, 1H), 3.92 (s, 1H), 3.80 – 3.63(m, 1H), 3.48 (dd, J = 64.9, 26.8 Hz, 1H), 2.81 (t, J = 22.9 Hz, 1H), 1.90 – 1.78 (m, 1H), 1.36 – 1.25 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 154.56 (s), 143.23 (s), 132.42 (s), 129.01 (s), 114.48 (t, J = 5.9 Hz), 107.42 (s), 104.59 –104.20 (m), 103.63 (s), 77.99 (s), 76.72 (s), 76.01 (s), 74.12 (s), 70.22(s), 61.31 (s), 55.70 (s).

[0120] Example 6:

[0121] Logarithmically growing human lung cancer A549 and colon cancer cells HCT-116, and normal human hepatocytes L02 were added to 96-well plates, with 100 μL per well containing approximately 3000 cells. Compound (1) obtained in Example 1 was added, along with icariin as a control. Three parallel wells were set for each group, and the plates were incubated at 37°C for 48 hours in a CO2 incubator. Four hours before the end of the experiment, 20 μL / well of MTT (20 mg / mL) solution was added, and the plates were incubated for another 4 hours. The culture medium was discarded, and 150 μL / well of DMSO was added. After the crystals dissolved, the OD value of each well was measured at 490 nm using a microplate reader. The half-maximal inhibitory concentration (IC50) was then calculated using GraphPad Prism software. 50 value).

[0122] The results are shown in Table 1 below.

[0123] Table 1. IC50 values ​​of the inhibitory effects of 5-glycosylated derivatives of icariin on the in vitro growth of A549, HCT-166, and L02 cells. 50

[0124]

[0125] The above descriptions are merely embodiments of the present invention, and common knowledge regarding specific structures and characteristics is not elaborated upon here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the structure 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 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. A 5-glycosylated derivative of cycloicariin, characterized in that, The structural formula is shown in equation (1). Equation (1), In the above formula, R1 represents H and C. 1-10 alkyl, benzyl, propargyl or C 1-6 Alicyclic group; R2 is α-D glucose or α-D galactose.

2. The method for preparing the 5-glycosylated derivative of cycloicariin according to claim 1, characterized in that, Includes the following steps: ， Step a: Icariin was refluxed with formic acid to obtain cyclic icariin A, the structural formula of which is shown in formula (2): Equation (2), Step b: Cycloic icariin A is dissolved in a solvent with a haloalkane R1X under the action of base B1, and then etherified under certain conditions to obtain 3-OR1 cycloicariin B, the structure of which is shown in formula (3): Equation (3), Step c: Dissolve 3-OR1 cycloicariin B in a solvent and react it with α-D-acetylated bromide under the catalysis of base B2 to obtain 3-OR1-5-peracetylated sugar C, the structural formula of which is shown in formula (4): Equation (4), Step d: Dissolve 3-OR1-5-peracetylated sugar C in a solvent, add base B3, and react under certain conditions to obtain 3-OR1-5-sugar compound D, whose structural formula is shown in formula (1): Equation (1) Where: R1 represents H and C 1-10 Alkyl, benzyl, propargyl, C 1-6 Alicyclic or aryl group; R2 is α-D glucose or α-D galactose; R3 is α-D acetylglucose or α-D acetylglucose.

3. The method for preparing the 5-glycosylated derivative of cycloicariin according to claim 2, characterized in that, The process also includes step e, in which 3-OR1-5-sugar compound D is dissolved in a solvent, a catalyst is added, and hydrogenation is carried out by catalytic addition to obtain compound (2), the structural formula of which is shown in formula (5). Where R1 is H or benzyl, and R2 is α-D-glucose.

4. The preparation method according to claim 2, characterized in that: The bases B1, B2, and B3 are each independently selected from sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or NaH.

5. The preparation method according to claim 2, characterized in that, The haloalkane R1X in step b refers to: fluorinated hydrocarbons, chlorinated hydrocarbons, bromine hydrocarbons, or iodinated hydrocarbons.

6. The preparation method according to claim 2, characterized in that: The solvents used in steps b, c, and d are each independently selected from: acetonitrile, dichloromethane, chloroform, acetone, tetrahydrofuran, DMF, or DMSO.

7. The preparation method according to claim 2, characterized in that: The etherification reaction conditions in step b are: temperature 25℃~120℃, reaction time 1~24 hours; the reaction conditions in step c are: -20℃~100℃, reaction time 1~48 hours; and the reaction conditions in step d are: 0~120℃, reaction time 0.5~12 hours.

8. The preparation method according to claim 3, characterized in that: The solvent in step e is acetonitrile, methanol, ethanol, isopropanol, water, tetrahydrofuran, ethyl acetate, DMF, or DMSO; the catalyst in step e is any one of 5% Mw Pd / C, 10% Mw Pd / C, 20% Mw Pd / C, PtO2, 10% Mw Pt / C, 20% Mw Pt / C, 10% Mw Pd(OH)2 / C, or 20% Mw Pd(OH)2 / C; the reaction conditions in step e are: stirring at 0–100°C for 0.5–12 hours.

9. The use of the 5-glycosylated derivative of cycloicariin according to claim 1 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 colon cancer or lung cancer.

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