Oleanolic acid derivative, preparation method and application thereof

Abstract

The application discloses a oleanolic acid derivative, a preparation method and application thereof, and has the structure shown in the formula I: wherein R1 is selected from H or -C=OR3; R3 is selected from C 1～6 alkyl; R2 is selected from -CONHN=CHR, -CONHNHCH2R, -CONHNHCOR, -C=N-NHCOR; R is selected from C 1～6 alkyl, styryl, C 3～12 aryl, halogen-containing C 1～6 alkyl, C 1～6 alkoxy, C 1～6 halogenated alkyl, nitro, hydroxyl, at least one substituted C 3～12 aryl. The application provides a series of novel oleanolic acid derivatives, experiments show that the oleanolic acid derivatives have good anti-influenza A H1N1 virus activity, and can be used for preparing medicines with anti-influenza A H1N1 virus activity.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, and in particular to an oleanolic acid derivative, its preparation method, and its application. Background Technology

[0002] Influenza viruses are classified into three types: A, B, and C. Influenza viruses discovered in recent years are classified as type D. These include human and animal influenza viruses. The structure of an influenza virus, from the outside in, can be divided into three parts: the envelope, matrix proteins, and the core. The viral core contains the genetic material storing viral information and the enzymes necessary for replicating this information. The matrix proteins form the viral outer shell skeleton; in fact, in addition to the matrix proteins (M1), the skeleton also contains membrane proteins (M2). The envelope is a phospholipid bilayer membrane surrounding the matrix proteins. This membrane originates from the host cell membrane. Mature influenza viruses bud from the host cell, wrap themselves around the host cell membrane, and then detach from the cell to infect the next target. Besides phospholipid molecules, there are two very important glycoproteins: hemagglutinin and neuraminidase.

[0003] Currently, the US FDA has approved only six antiviral drugs for influenza: two M2 proton channel inhibitors (amantadine and rimantadine), three neuraminidase inhibitors (zanamivir, oseltamivir, and peramivir), and one RNA-dependent RNA polymerase inhibitor (sovruza). Antiviral drugs targeting neuraminidase can be classified structurally into the following categories: cyclohexene derivatives, pyran derivatives, pyrrolidine derivatives, benzoic acid derivatives, and natural product derivatives. Over the years, various antiviral drugs have revealed certain shortcomings. For example, oseltamivir, after years of use, has developed resistance in clinical practice, gradually diminishing its clinical value. Furthermore, the development of vaccines is often delayed, making it difficult to cope with large-scale outbreaks of novel influenza viruses.

[0004] Therefore, it is necessary to develop a compound with a novel structure and better anti-H1N1 influenza virus effect. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention proposes an oleanolic acid derivative, which has a novel structure and good anti-H1N1 influenza virus activity, and can be used to prepare drugs with anti-H1N1 influenza virus activity.

[0006] A second aspect of the present invention also provides a method for preparing an oleanolic acid derivative.

[0007] A third aspect of the present invention also provides a drug for treating H1N1 influenza A virus.

[0008] The fourth aspect of the present invention also provides an application of an oleanolic acid derivative.

[0009] An oleanolic acid derivative according to a first aspect embodiment of the present invention has the structure shown in Formula I:

[0010]

[0011] Wherein, R1 is selected from H or -COR3; R3 is selected from C 1～6 Alkyl groups;

[0012] R2 is selected from -CONHN=CHR, -CONHNHCH2R, -CONHNHCOR, and -CH=N-NHCOR;

[0013] R is selected from C 1～6 Alkyl, styrene, C 3～12 Aryl groups, containing halogenated compounds, C 1～6 alkyl, C 1～6 alkoxy, C 1～6 At least one of the alkyl, nitro, and hydroxyl groups substituted with C 3～12 Aryl groups.

[0014] The oleanolic acid derivatives according to embodiments of the present invention have at least the following beneficial effects:

[0015] This invention provides a series of novel oleanolic acid derivatives, and the EC of oleanolic acid derivatives... 50 The values ​​are all below 10 μM, which shows a good inhibitory effect on the H1N1 influenza virus and can be used to prepare drugs against the H1N1 influenza virus.

[0016] According to some embodiments of the present invention, the C 3～12 The aryl groups include phenyl, thiophene, pyridyl, quinolinyl, isoquinolinyl, furanyl, imidazolyl, pyrroleyl, and thiazolyl.

[0017] According to some embodiments of the present invention, the oleanolic acid derivative is selected from one of the following structures:

[0018]

[0019]

[0020]

[0021] The method for preparing oleanolic acid derivatives according to a second aspect embodiment of the present invention includes the following steps:

[0022] The first reaction is carried out between compound III and compound 1;

[0023] Alternatively, compound III, compound 2, and an organic base can undergo a second reaction;

[0024] Alternatively, the compound of formula V and compound 3 may be subjected to a third reaction. Optionally, the method may further include: reacting the product of the third reaction with sodium cyanoborohydride in a fourth reaction.

[0025] The structural formulas of compound III, compound 1, compound 2, compound 3, compound V, and the product after the third reaction are as follows:

[0026]

[0027] According to some embodiments of the present invention, the first reaction satisfies at least one of the following conditions:

[0028] The reaction temperature is 0℃~70℃;

[0029] The reaction time for ii is 6.5h to 11.5h.

[0030] According to some embodiments of the present invention, the raw materials for the first reaction further include an organic solvent, wherein the organic solvent includes ethanol.

[0031] According to some embodiments of the present invention, after the first reaction is completed, a post-processing is further included, the post-processing steps being as follows: adding water to the system, precipitating a solid, filtering and washing with n-hexane, and dissolving the solid in a small amount of ethyl acetate for recrystallization.

[0032] According to some embodiments of the present invention, the molar ratio of compound III to compound 1 is 1:(1-2).

[0033] According to some embodiments of the present invention, the second reaction satisfies at least one of the following conditions:

[0034] The reaction temperature is 25℃~60℃;

[0035] The reaction time for step ii is 6.5 h to 11.5 h.

[0036] The molar ratio of compound III, compound 2, and organic base of formula iii is 1:(2-4):(1-2).

[0037] According to some embodiments of the present invention, the raw materials for preparation in the second reaction further include an organic solvent, said organic solvent including at least one of N,N-dimethylformamide, toluene, and 1,4-dioxane.

[0038] According to some embodiments of the present invention, after the second reaction is completed, a post-treatment is further included. The post-treatment steps are as follows: water is added to the completed system, extraction is performed with ethyl acetate, washing is performed with saturated brine and drying is done with anhydrous sodium sulfate, and then column chromatography is used to obtain the final product.

[0039] According to some embodiments of the present invention, the compound of formula III is prepared by the following method:

[0040] The compound of formula II is reacted with an organic solvent and hydrazine hydrate to obtain the product.

[0041] The structural formula of compound II is as follows:

[0042]

[0043] According to some embodiments of the present invention, the reaction conditions include: a temperature of -20 to 0°C and a time of 5 to 12 hours.

[0044] According to some embodiments of the present invention, the organic solvent includes at least one of dichloromethane and toluene.

[0045] According to some embodiments of the present invention, the raw materials for the above reaction also include a mutual solvent, which includes tetrahydrofuran and / or 1,4-dioxane.

[0046] According to some embodiments of the present invention, the molar ratio of the compound of formula II to hydrazine hydrate is 1:(8-12).

[0047] According to some embodiments of the present invention, the compound of formula II is prepared by the following method:

[0048] Oleanolic acid, oxaloyl chloride and N,N-dimethylformamide were reacted to give compound II;

[0049] The structural formula of oleanolic acid is as follows:

[0050]

[0051] According to some embodiments of the present invention, the reaction conditions include: a reaction temperature of -20°C to 0°C and a reaction time of 6h to 14h.

[0052] According to some embodiments of the present invention, the raw materials for the preparation of the reaction further include an organic solvent selected from dichloromethane and / or toluene.

[0053] According to some embodiments of the present invention, the molar ratio of oleanolic acid to oxaloyl chloride is 1:(2-4).

[0054] According to some embodiments of the present invention, the N,N-dimethylformamide is used for catalysis, and its amount is 0.1% to 1% of the molar amount of oleanolic acid.

[0055] According to some embodiments of the present invention, after the reaction is completed, a post-processing is further included. The post-processing process is as follows: the oil pump is used to perform a vacuuming operation, the mixture is dissolved in a small amount of dichloromethane and then vacuumed, and the operation is repeated three times to obtain compound II.

[0056] According to some embodiments of the present invention, the third reaction satisfies at least one of the following conditions:

[0057] The reaction temperature is 50℃~100℃;

[0058] The reaction time is 5 to 8 hours.

[0059] The molar ratio of compound V and compound 3 of formula iii is 1:(1 to 1.5).

[0060] According to some embodiments of the present invention, the compound of formula V is prepared by the following reaction:

[0061] The compound of formula IV, the Dess-Martin reagent, and the solvent are reacted at -10 to 10°C to obtain the product.

[0062]

[0063] According to some embodiments of the present invention, the reaction time is 3 to 6 hours.

[0064] According to some embodiments of the present invention, the solvent includes dichloromethane.

[0065] According to some embodiments of the present invention, the ratio of the compound of formula IV, the Desmond-Martin reagent and the solvent is (10-20) mmol / L : (15-30) mmol / L : (70-140) mL.

[0066] According to some embodiments of the present invention, the compound of formula IV is prepared by the following method:

[0067] The compound of formula ③ is hydrolyzed with an organic solvent under alkaline conditions to obtain the product.

[0068] The structural formula of compound ③ is as follows:

[0069]

[0070] According to some embodiments of the present invention, the organic solvent includes tetrahydrofuran and / or methanol.

[0071] According to some embodiments of the present invention, the compound of formula ③ is prepared by the following method:

[0072] The compound of formula ②, acetic anhydride, and dichloromethane were mixed and reacted, and the mixture was then obtained by column chromatography.

[0073] The structural formula of compound ② is as follows:

[0074]

[0075] According to some embodiments of the present invention, the raw materials for the reaction further include 4-dimethylaminopyridine as a condensing agent and triethylamine as an acid-binding agent.

[0076] According to some embodiments of the present invention, the reaction conditions include: 20°C-25°C; and the reaction time is 5-12 hours.

[0077] According to some embodiments of the present invention, the molar ratio of the compound of formula ②, acetic anhydride, 4-dimethylaminopyridine, and triethylamine is (10-20):(50-100):(1-2):(100-200).

[0078] According to some embodiments of the present invention, the compound of formula ② is prepared by the following method:

[0079] Oleanolic acid, sodium borohydride and iodine were reacted, and the compound of formula ② was obtained by column chromatography.

[0080] According to some embodiments of the present invention, the reaction conditions include: a temperature of 25°C-40°C and a reaction time of 6-14 hours.

[0081] According to some embodiments of the present invention, the molar ratio of oleanolic acid, sodium borohydride and iodine is (10-20):(100-200):(35-70).

[0082] According to some embodiments of the present invention, the fourth reaction satisfies at least one of the following conditions:

[0083] The reaction temperature is 0℃~25℃;

[0084] The reaction time is 5 to 8 hours.

[0085] The molar ratio of the product after the third reaction to sodium cyanoborohydride is 1:(5-10).

[0086] A third aspect of the present invention provides a drug for treating H1N1 influenza A virus, comprising the oleanolic acid derivatives described above.

[0087] The fourth aspect of this invention provides the use of the oleanolic acid derivatives described above in the preparation of anti-influenza virus drugs.

[0088] According to some embodiments of the present invention, the influenza virus includes influenza A (H1N1) virus.

[0089] Definitions and general terms

[0090] “C 1～6 "alkyl" indicates an alkyl group with a total number of 1-6 carbon atoms, including C64. 1-6 straight-chain alkyl, C 1-6 Branched alkyl groups and C 3-6 The cycloalkyl group can be, for example, a straight-chain alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched-chain alkyl group with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkyl group with a total number of carbon atoms of 3, 4, 5 or 6, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc.

[0091] “C 1～6 "halogenated alkyl" and "C" 1～6 "alkyl" has a similar definition, the difference being that "C" 1～6 Any H atom in the "halogenated alkyl group" is replaced by any halogen.

[0092] “C 1-6 "alkoxy group" refers to an alkoxy group with a total number of 1-6 carbon atoms, including C64 and C64. 1-6 straight-chain alkoxy, C 1-6 Branched alkoxy groups and C 2-6 The cycloalkoxy group can be, for example, a straight-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, a branched-chain alkoxy group with a total number of carbon atoms of 1, 2, 3, 4, 5 or 6, or a cycloalkoxy group with a total number of carbon atoms of 2, 3, 4, 5 or 6, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0093] "Halogen" includes any one or more of fluorine, chlorine, bromine, and iodine.

[0094] “C 3～12 "Aryl" indicates a monocyclic or fused polycyclic group with a total of 3 to 12 carbon atoms, or containing one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining ring atoms being C, possessing a fully conjugated π-electron system. Examples include benzene, naphthalene, indene, fluorene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine, pyridine, pyridone, imididine, pyrazine, pyridazine, indole, azaindole, benzimidazole, benzotriazole, indoline, indoleone, quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, etc.

[0095] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention. Detailed Implementation

[0096] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0097] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0098] Example 1

[0099] This example provides an oleanolic acid derivative, the reaction equation of which is as follows, and the preparation steps are as follows:

[0100]

[0101] S1. Accurately weigh 4.56 g (10 mmol) of oleanolic acid using a 0.01 g balance and pour it into a 250 mL round-bottom flask. Then, use a 50 mL syringe to repeatedly draw ultra-dry dichloromethane and add it to the round-bottom flask while stirring at room temperature. Transfer the reaction system to an ice bath and stir for 5 min. Accurately weigh 2.5 mL of oxaloyl chloride using a 5 mL syringe and add it dropwise to the round-bottom flask under an ice bath. After the addition is complete, stir for 10 min. Then, add 3 drops of N,N-dimethylformamide and then stir at room temperature for 8 h to obtain compound II.

[0102] S2. 4.74 g (10 mmol) of compound II was dried using an oil pump (2 mL of ultra-dry dichloromethane was added several times during this process to dissolve the compound before drying). 25 mL of dry dichloromethane was added. 5.16 mL (100 mmol) of 85% hydrazine hydrate was added to a 250 mL round-bottom flask using a 10 mL disposable syringe. 100 mL of tetrahydrofuran was accurately measured and mixed with 85% hydrazine hydrate using a graduated cylinder. The mixture was stirred at -20 °C for 30 min. Then, compound II was added dropwise to the 85% hydrazine hydrate solution using a 20 mL syringe. The mixture was reacted at -20 °C for 8 h. After the reaction was complete, the solvent was removed from the reaction solution under vacuum. After quenching with water, the mixture was extracted three times with 3 x 50 mL ethyl acetate. The combined organic phases were washed successively with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under vacuum to obtain compound III.

[0103] S3. Weigh 188 mg (0.4 mmol) of compound III and 0.4 mmol of p-trifluoromethylbenzaldehyde into a 10 mL reaction tube using a 0.01 g balance. Add 8 mL of anhydrous ethanol and stir at room temperature for 8 hours. After the reaction is complete, turn the reaction solution under vacuum to a minimum volume and pour in 5 mL of ice water. A solid precipitates out. After filtration, wash the solid with a large amount of n-hexane, dry at room temperature, and recrystallize from ethyl acetate to obtain the oleanolic acid derivative (white solid, yield 87.4%).

[0104] The NMR data of oleanolic acid derivatives are as follows:

[0105] 1 H NMR (500MHz, CDCl3) δ9.13(s,1H),8.24(s,1H),7.83(d,J=8.2Hz,3H),7.63(d,J=8.5Hz ,3H),5.55(t,J=3.6Hz,1H),3.21(dd,J=11.3,4.3Hz,1H),2.63(d,J=10.6Hz,1H),2.11 –1.98(m,3H),1.88–1.64(m,6H),1.59–1.52(m,3H),1.48–1.22(m,8H),1.20(s,3H),1. 11(d,J=13.9Hz,2H),0.98(s,3H),0.93(s,6H),0.89(s,3H),0.76(s,3H),0.73(s,3H). 13 C NMR (126MHz, CDCl3) δ175.3, 146.1, 145.4, 137.5, 164.1 (q, J = 32.8Hz), 127.9, 125.7 (q, J = 3.8Hz), 124.0 (q, J = 273.0Hz), 123.8, 79.0, 55.2, 47. 6,46.8,46.7,42.3,42.1,39.6,38.9,38.6,37.1,34.1,33.0,32.3,32.2 ,30.8,28.2,27.4,27.3,26.0,24.3,23.8,23.7,18.3,17.1,15.7,15.5. 19 F NMR (471MHz, CDCl3) δ -62.80.

[0106] Example 2

[0107] Example 2 provides an oleanolic acid derivative with the following structural formula. The preparation method is the same as in Example 1, except that the raw material in step S3 is 4-methoxybenzaldehyde.

[0108]

[0109] Its NMR data are as follows:

[0110] White solid, yield 90.8%; 1H NMR (500MHz, CDCl3) δ9.04(s,1H),7.99(s,1H),7.63(d,J=8.9Hz,2H),6.85(d,J=8.9Hz,2 H),5.50(t,J=3.7Hz,1H),3.78(s,3H),3.17(dd,J=11.3,4.5Hz,1H),2.61(d,J=8.1Hz,1H) ,2.03–1.94(m,3H),1.84–1.60(m,6H),1.57–1.49(m,3H),1.47–1.18(m,8H),1.15(s,3H) ,1.04(d,J=13.9Hz,2H),0.94(s,3H),0.89(s,6H),0.84(s,3H),0.72(s,3H),0.69(s,3H). 13 C NMR (126MHz, CDCl3) δ174.6,161.4,147.5,145.3,129.3,126.5,123.4,114.1,78.8,55.3,55.1,47.5,46.7,46.3,42.1,41 .9,39.5,38.7,38.5,36.9,34.0,33.0,32.2,32.1,30.7,28.1,27.3,27.1,25.9,24.0,23.7,23.6,18.2,17.0,15.6,15.4.

[0111] Example 3

[0112] Example 3 provides an oleanolic acid derivative with the following structural formula. The preparation method is the same as in Example 1, except that the raw material in step S3 is pyridine-2-carboxaldehyde.

[0113]

[0114] Its NMR data are as follows:

[0115] White solid, yield 63.2%. 1H NMR (500MHz, CDCl3) δ9.27 (s, 1H), 8.55 (d, J = 4.9Hz, 1H), 8.12 (d, J = 8.0Hz, 1H), 8.04 (s, 1H), 7.69 (td,J=7.7,1.8Hz,2H),7.25–7.23(m,1H),5.51(t,J=3.7Hz,1H),3.18(dd,J=11.3,4.4Hz,1H),2.6 1(d,J=8.1Hz,1H),2.07–1.94(m,3H),1.87–1.60(m,6H),1.57(d,J=3.8Hz,3H),1.51–1.21(m,8H) ,1.17(s,3H),1.14–1.02(m,2H),0.95(s,3H),0.91(s,6H),0.85(s,3H),0.73(s,3H),0.70(s,3H). 13 C NMR (126MHz, CDCl3) δ175.2,153.0,149.3,147.2,145.3,136.7,124.5,123.9,121.5,78.9,55.1,47.6,46.8,46.6,42.2 ,42.0,39.5,38.8,38.6,37.0,34.1,33.0,32.2,30.8,28.2,27.3,27.2,25.9,24.3,23.8,23.7,18.3,17.0,15.6,15.5.

[0116] Example 4

[0117] Example 4 provides an oleanolic acid derivative with the following structural formula. The preparation method is the same as in Example 1, except that the raw material in step S3 is o-hydroxybenzaldehyde.

[0118]

[0119] Its NMR data are as follows:

[0120] Pale yellow solid, yield 64.2%. 1H NMR (500MHz, DMSO-d6) δ11.43(d,J=7.6Hz,1H),10.92(s,1H),8.52(s,1H),7.42(d,J=6.6Hz,1H),7.26(t,J=7.7Hz,1H ),6.88(t,J=7.0Hz,2H),5.27(t,J=3.8Hz,1H),4.28(d,J=5.2Hz,1H),3.00–2.96(m,1H),2.91(s,1H),2.01(d,J=9.7H z,1H),1.81(d,J=5.1Hz,2H),1.69(t,J=13.5Hz,2H),1.60–1.34(m,13H),1.27(t,J=13.8Hz,1H),1.17(d,J=12.3Hz,2 H),1.10(s,3H),0.98(d,J=13.1Hz,1H),0.92(s,3H),0.89(s,3H),0.87(s,3H),0.80(s,3H),0.64(s,3H),0.61(s,3H). 13 C NMR (126MHz, DMSO) δ172.6,157.4,147.4,143.8,131.0,129.7,121.8,119.2,118.6,116.4,76.9,54.8,47.1,45.7,45.2 ,41.2,38.4,38.1,36.6,33.4,32.9,32.3,32.2,30.4,28.2,27.1,27.0,25.8,23.6,23.0,22.0,18.0,16.7,16.0,15.1.

[0121] Example 5

[0122] Example 5 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0123]

[0124] Its NMR data are as follows:

[0125] Green solid, yield 81.4%. 1H NMR (500MHz, CDCl3) δ11.04(s,1H),9.00(s,1H),8.27(s,1H),7.22(dd,J=8.8,2.6Hz,1H),7.16( d,J=2.6Hz,1H),6.92(d,J=8.8Hz,1H),5.55(t,J=3.7Hz,1H),3.21(dd,J=11.4,4.4Hz,1H),2.62( d,J=7.7Hz,1H),2.11–1.98(m,3H),1.84–1.63(m,6H),1.59–1.52(m,3H),1.48–1.22(m,8H),1.20 (s,3H),1.11(d,J=13.8Hz,2H),0.98(s,3H),0.93(s,6H),0.90(s,3H),0.76(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ174.8,157.3,149.5,145.4,131.6,130.0,124.1,123.9,118.9,118.7,79.0,55.2,47.6,46.7,42. 3,41.9,39.6,38.9,38.6,37.1,34.1,33.0,32.3,32.2,30.9,28.2,27.3,27.3,26.0,24.4,23.8,18.3,17.0,15.7,15.6.

[0126] Example 6

[0127] Example 6 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0128]

[0129] Its NMR data are as follows:

[0130] White solid, yield 80.5%. 1H NMR (500MHz, CDCl3) δ9.00 (s, 1H), 8.01 (s, 1H), 6.95 (s, 2H), 5.54 (t, J = 3.8Hz, 1H), 3 .88(s,6H),3.86(s,3H),3.21(dd,J=11.4,4.4Hz,1H),2.62(d,J=9.3Hz,1H),2.09–1. 98(m,3H),1.88–1.64(m,6H),1.58–1.51(m,3H),1.48–1.24(m,8H),1.19(s,3H),1.0 9(d,J=13.9Hz,2H),0.97(s,3H),0.92(s,6H),0.89(s,3H),0.75(s,3H),0.73(s,3H). 13 C NMR (126MHz, CDCl3) δ174.9,153.5,147.7,145.6,140.3,129.4,123.6,104.9,79.0,61.1,56.4,55.2,47.6,46.8,46.6,42.3 ,42.2,39.6,38.9,38.6,37.1,34.1,33.1,32.3,32.3,30.8,28.2,27.4,27.2,26.0,24.2,23.8,23.7,18.4,17.1,15.7,15.5.

[0131] Example 7

[0132] Example 7 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0133]

[0134] Its NMR data are as follows:

[0135] Colorless, transparent solid, yield 81.4%. 1H NMR (500MHz, DMSO-d6) δ10.32(s,1H),9.86(s,1H),8.23(s,1H),7.47(d,J=8.7Hz,2H),6.80(d,J=8.7Hz,2H), 5.28(t,1H),4.28(d,J=5.2Hz,1H),2.98(dt,J=10.0,5.5Hz,1H),2.91(d,J=9.4Hz,1H),2.01–1.97(m,1H),1.8 2(d,J=5.0Hz,2H),1.68(d,J=13.2Hz,2H),1.59–1.35(m,13H),1.27(d,J=11.7Hz,1H),1.19–1.15(m,2H),1.10 (s,3H),0.96(d,J=13.5Hz,1H),0.91(s,3H),0.88(s,3H),0.88(s,3H),0.81(s,3H),0.65(s,3H),0.62(s,3H). 13 C NMR (126MHz, DMSO-d6) δ172.4,159.1,146.8,144.0,128.6,125.6,121.7,115.6,76.9,54.8,47.1,45.9,45.2,41. 2,38.4,38.1,36.6,33.5,32.9,32.3,32.2,30.4,28.2,27.1,27.0,25.7,23.6,23.0,22.1,18.0,16.9,16.0,15.1.

[0136] Example 8

[0137] Example 8 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0138]

[0139] Its NMR data are as follows:

[0140] White solid, yield 76.5%. 1H NMR(500MHz, CDCl3) δ8.83(d,J=17.9Hz,1H),8.75(s,1H),6.99(t,J=3.2Hz,2H),5. 50(t,J=4.3Hz,1H),3.21(d,J=11.4Hz,1H),2.59(d,J=10.5Hz,1H),2.08–1.97(m,3 H),1.81–1.63(m,6H),1.54(d,J=8.8Hz,3H),1.48–1.23(m,8H),1.19(s,3H),1.09( d,J=14.1Hz,2H),0.98(s,3H),0.92(s,6H),0.91(s,3H),0.77(s,3H),0.74(s,3H). 13 C NMR (126MHz, CDCl3) δ175.5,145.1,143.7,141.3,130.4,130.3,123.9,116.5,79.1,55.2,47.7,46.9,46.8,42.2,42.0 ,39.6,38.9,38.6,37.1,34.2,33.1,32.4,32.3,30.8,28.2,27.4,27.3,26.0,24.2,23.8,23.7,18.4,17.0,15.7,15.5.

[0141] Example 9

[0142] Example 9 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0143]

[0144] Its NMR data are as follows:

[0145] White solid, yield 88.4%. 1H NMR (500MHz, CDCl3) δ9.04(s,1H),8.10(s,1H),7.59(d,J=8.6Hz,2H),7.51(d,J=8.6H z,2H),5.54(t,J=3.7Hz,1H),3.21(dd,J=11.4,4.4Hz,1H),2.62(d,J=8.3Hz,1H),2.09 –1.97(m,3H),1.88–1.63(m,6H),1.58–1.52(m,3H),1.48–1.24(m,8H),1.19(s,3H),1. 09(d,J=13.9Hz,2H),0.98(s,3H),0.93(s,6H),0.89(s,3H),0.76(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ175.1,146.6,145.5,133.0,132.0,129.2,124.8,123.7,79.0,55.2,47.6,46.8,46.7,42.3,42.1 ,39.6,38.9,38.6,37.1,34.1,33.1,32.3,32.3,30.9,28.2,27.4,27.3,26.0,24.3,23.8,23.7,18.4,17.1,15.7,15.5.

[0146] Example 10

[0147] Example 10 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0148]

[0149] Its NMR data are as follows:

[0150] White solid, yield 88.4%. 1H NMR (500MHz, CDCl3) δ9.04 (s, 1H), 8.11 (s, 1H), 7.70 (d, J = 3.5Hz, 2H), 7.05 (t, J = 8.6Hz ,2H),5.53(t,J=3.7Hz,1H),3.20(dd,J=11.4,4.5Hz,1H),2.62(d,J=8.5Hz,1H),2.07–1 .97(m,3H),1.88–1.60(m,6H),1.55(d,J=15.4Hz,3H),1.47–1.21(m,8H),1.19(s,3H),1 .08(d,J=13.9Hz,2H),0.97(s,3H),0.92(s,6H),0.88(s,3H),0.75(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ175.0, 164.1 (d, J = 250.7Hz), 146.7, 145.5, 130.2 (d, J = 3.8Hz), 129.6 (d, J = 8.8Hz), 123.66, 115.9 (d, J = 21.4Hz), 79.0, 55.1, 47.6,46.8,46.6,42.2,42.1,39.6,38.9,38.6,37.0,34.1,33.0,32.3,32 .2,30.8,28.2,27.3,27.2,25.9,24.2,23.8,23.7,18.3,17.1,15.6,15.5. 19 F NMR (471MHz, CDCl3) δ -109.59.

[0151] Example 11

[0152] Example 11 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0153]

[0154] Its NMR data are as follows:

[0155] White solid, yield 73.8%. 1H NMR (500MHz, CDCl3) δ8.98(s,1H),7.81(d,J=9.1Hz,1H),7.44(d,J=7.0Hz,2H),7.35(t,J=7.4Hz,2H),7.30( t,J=7.2Hz,1H),7.04(dd,J=16.1,9.1Hz,1H),6.86(d,J=16.1Hz,1H),5.52(t,J=3.7Hz,1H),3.21(dd,J=11.4 ,4.4Hz,1H),2.59(d,J=8.0Hz,1H),2.07–1.98(m,3H),1.89–1.63(m,6H),1.56(d,J=18.4Hz,3H),1.48–1.22( m,8H),1.19(s,3H),1.08(d,J=14.1Hz,2H),0.98(s,3H),0.92(s,6H),0.90(s,3H),0.76(s,3H),0.73(s,3H). 13 C NMR (126MHz, CDCl3) δ174.8,148.9,145.6,139.7,135.9,129.2,129.0,127.2,125.5,123.6,79.0,55.1,47.6,46.8,46.4,42. 2,42.1,39.5,38.8,38.6,37.0,34.1,33.0,32.2,32.2,30.8,28.2,27.3,27.2,25.9,24.2,23.8,23.7,18.3,17.0,15.6,15.5.

[0156] Example 12

[0157] Example 12 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0158]

[0159] Its NMR data are as follows:

[0160] White solid, yield 51.6%. 1H NMR (500MHz, DMSO-d6) δ10.02(s,1H),7.58(t,J=5.8Hz,1H),5.28(t,J=3.8Hz,1H),4.29(d,J=5.2Hz,1H),3.01–2. 97(m,1H),2.84(d,J=8.8Hz,1H),2.06(q,J=6.0Hz,2H),1.99–1.93(m,1H),1.79(dd,J=13.5,6.8Hz,3H),1.65(dd, J=20.4,13.6Hz,2H),1.56–1.42(m,9H),1.38–1.24(m,4H),1.18(d,J=12.6Hz,1H),1.13(d,J=5.1Hz,1H),1.09(s, 3H),0.95–0.92(m,3H),0.90(s,3H),0.89(s,3H),0.89(s,5H),0.88(s,3H),0.83(s,3H),0.67(s,3H),0.60(s,3H). 13 C NMR (126MHz, DMSO) δ172.2,150.1,144.0,121.7,76.8,54.8,47.1,45.9,45.0,41.2,40.7,38.4,38.1,36.6 ,33.5,32.9,32.3,32.1,30.4,28.2,27.0,27.0,26.3,25.7,23.6,23.0,22.2,22.2,18.0,16.8,16.0,15.0.

[0161] Example 13

[0162] Example 13 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0163]

[0164] Its NMR data are as follows:

[0165] Green solid, yield 83.8%. 1H NMR (500MHz, CDCl3) δ9.44(s,1H),8.94–8.91(m,2H),8.48(d,J=8.5Hz,1H),8.14(d,J=8.5Hz,1H),7. 76–7.71(m,2H),7.59(t,J=7.7Hz,1H),5.60(t,J=3.8Hz,1H),3.20(dd,J=11.4,4.4Hz,1H),2.71(d,J= 9.8Hz,1H),2.13–2.01(m,3H),1.90–1.65(m,6H),1.61(d,J=9.9Hz,3H),1.57–1.27(m,8H),1.20(s,3 H),1.11(d,J=14.1Hz,2H),0.96(s,3H),0.94(d,J=4.8Hz,6H),0.88(s,3H),0.76(s,3H),0.74(s,3H). 13 C NMR (126MHz, CDCl3) δ175.4,150.0,148.7,145.3,144.4,137.6,130.2,129.6,127.6,125.4,123.8,123.8,119.7,78.8,55.1,47.5,46.7 ,46.6,42.1,41.9,39.5,38.8,38.5,37.0,34.0,32.9,32.2,32.1,30 .7,28.1,27.3,27.1,25.9,24.2,23.7,23.6,18.2,17.0,15.6,15.3.

[0166] Example 14

[0167] Example 14 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0168]

[0169] Its NMR data are as follows:

[0170] White solid, yield 81.6%. 1H NMR(500MHz, CDCl3)δ9.08(s,1H),8.16(s,1H),7.44(d,J=8.8Hz,2H),7.35–7.31(m,1H),7 .08–7.04(m,1H),5.54(t,J=3.8Hz,1H),3.20(dd,J=11.4,4.4Hz,1H),2.62(d,J=8.1Hz,1H) ,2.09–1.98(m,3H),1.87–1.64(m,6H),1.61(d,J=3.5Hz,3H),1.54–1.23(m,8H),1.19(s,3H ),1.09(d,J=13.9Hz,2H),0.97(s,3H),0.92(s,6H),0.89(s,3H),0.75(s,3H),0.73(s,3H). 13 C NMR (126MHz, CDCl3) δ175.1,163.1(d,J=245.7Hz),146.6,145.4,136.4(d,J=7 .6Hz),130.3(d,J=7.6Hz),123.8,117.3(d,J=21.4Hz),114.0(d,J=22.7Hz),79 .0,55.2,47.6,46.8,46.7,42.3,42.1,39.6,38.9,38.6,37.0,34.1,33.0,32.3,32.2,30.8,28.2,27.3,27.2,26.0,24.3,23.8,23.7,18.3,17.1,15.7,15.5. 19 F NMR (471MHz, CDCl3) δ-112.7.

[0171] Example 15

[0172] Example 15 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0173]

[0174] Its NMR data are as follows:

[0175] White solid, yield 83.5%. 1H NMR(500MHz, CDCl3)δ9.12(s,1H),8.00(s,1H),7.52(d,J=8.5Hz,1H),7.05–6.99(m,2 H),5.52(t,J=3.8Hz,1H),3.89(s,3H),3.19(dd,1H),2.63(d,J=8.0Hz,1H),2.07–1.96 (m,3H),1.85–1.60(m,6H),1.55(d,J=25.2Hz,3H),1.52–1.20(m,8H),1.17(s,3H),1. 07(d,J=13.9Hz,2H),0.95(s,3H),0.90(s,6H),0.86(s,3H),0.73(s,3H),0.71(s,3H). 13 C NMR (126MHz, CDCl3) δ175.1, 154.1 (d, J = 252.0Hz), 148.4 (d, J = 10.1Hz), 146.8, 14 5.6,130.6(d,J=3.8Hz),123.7,122.1(d,J=7.6Hz),116.0(d,J=20.2Hz),110.7,7 9.0,56.5,55.2,47.6,46.9,46.6,42.3,42.2,39.6,38.9,38.6,37.1,34.1,33.1,32.3,32.3,30.9,28.2,27.4,27.3,26.0,24.3,23.8,23.7,18.4,17.1,15.7,15.5. 19 F NMR (471MHz, CDCl3) δ-130.9.

[0176] Example 16

[0177] Example 16 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0178]

[0179] Its NMR data are as follows:

[0180] White solid, yield 84.4%. 1H NMR (500MHz, CDCl3) δ9.06 (s, 1H), 8.17 (s, 1H), 7.60 (t, J = 8.8Hz, 1H), 7.38 (s, 1H), 7. 16(dd,1H),5.53(t,J=3.7Hz,1H),3.21(dd,J=11.4,4.4Hz,1H),2.62(d,J=8.5Hz,1H), 2.08–1.97(m,3H),1.86–1.62(m,6H),1.54(t,3H),1.48–1.24(m,8H),1.19(s,3H),1. 09(d,J=13.9Hz,2H),0.97(s,3H),0.92(s,6H),0.89(s,3H),0.76(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ175.1, 152.2 (dd, J1=12.6Hz, J2=123.5Hz), 150.1 (dd, J1=11.3Hz, J2=118.4H z),145.7(dd,J1=5.0Hz,J2=7.6Hz),145.3,131.3,124.3,123.7,117.5(d,J=17.6Hz),115.8(d,J=1 8.9Hz),78.9,77.3,77.2,77.0,76.8,55.1,47.5,46.7,46.6,42.2,42.0,39.5,38.8,38.5,36.9,3 4.0,32.9,32.2,32.1,30.7,30.2,28.1,27.2,27.1,25.8,24.2,23.7,23.6,18.2,16.9,15.5,15.4. 19 F NMR (471MHz, CDCl3) δ -134.3 (d, J = 18.84Hz), -136.9 (d, J = 18.84Hz).

[0181] Example 17

[0182] Example 17 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0183]

[0184] Its NMR data are as follows:

[0185] White solid, yield 84.3%. 1H NMR (500MHz, CDCl3) δ9.11 (s, 1H), 8.00 (s, 1H), 7.60 (d, J = 5.2Hz, 1H), 7.41 (dt, J = 5.4, 2.6Hz, 1H),6.95(t,J=8.9Hz,1H),5.51(t,J=3.7Hz,1H),3.18(dd,1H),2.62(d,J=8.2Hz,1H),2.22(s ,3H),2.05–1.94(m,3H),1.84–1.61(m,6H),1.56(d,J=7.4Hz,3H),1.48–1.19(m,8H),1.16(s, 3H),1.05(d,J=14.1Hz,2H),0.95(s,3H),0.89(s,6H),0.85(s,3H),0.73(s,3H),0.69(s,3H). 13 C NMR (126MHz, CDCl3) δ174.7,162.6(d,J=249.5Hz),146.6,145.2,130.5(d,J=6.3Hz),1 29.7(d,J=6.3Hz),127.2(d,J=7.6Hz),125.4(d,J=18.9Hz),123.4,115.2(d,J=22.7Hz ),78.7,55.0,47.5,46.6,46.3,42.0,41.8,39.4,38.7,38.5,36.9,34.0,32.9,32.2,32.1,30.7,28.1,27.2,27.1,25.8,23.9,23.6,23.6,18.2,17.0,15.6,15.4,14.4,14.4. 19 F NMR (471MHz, CDCl3) δ-113.8.

[0186] Example 18

[0187] Example 18 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0188]

[0189] Its NMR data are as follows:

[0190] White solid, yield 86.3%. 1H NMR(500MHz, CDCl3)δ9.11(s,1H),8.33(s,1H),7.90(t,1H),6.90–6.83(m,2H),5.55 (t,J=3.8Hz,1H),3.20(dd,J=11.6,4.4Hz,1H),2.63(d,J=8.2Hz,1H),2.40(s,3H),2. 07–1.97(m,3H),1.88–1.63(m,6H),1.52(d,J=13.9Hz,3H),1.47–1.20(m,8H),1.18( s,3H),1.06(t,2H),0.96(s,3H),0.92(s,6H),0.87(s,3H),0.75(s,3H),0.74(s,3H). 13 C NMR (126MHz, CDCl3) δ174.8, 163.6 (d, J = 249.5Hz), 145.5, 145.4, 139.4 (d, J = 8.8Hz), 129.3(d,J=10.1Hz), 128.2(d,J=2.5Hz), 123.6, 117.2(d,J=21.4Hz), 113.5(d,J=21. 4Hz),78.8,55.1,47.5,46.7,46.3,42.1,42.0,39.5,38.8,38.5,37.0,34.1,33.0,32 .1,32.1,30.8,28.1,27.3,27.1,25.9,24.1,23.7,23.6,19.4,18.2,17.1,15.6,15.4. 19 F NMR (471MHz, CDCl3) δ-110.8.

[0191] Example 19

[0192] Example 19 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0193]

[0194] Its NMR data are as follows:

[0195] White solid, yield 68.7%. 1H NMR (500MHz, CDCl3) δ9.41 (s, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.49 (d, J = 8.6Hz, 1H), 6 .94(td,2H),5.53(t,J=3.8Hz,1H),3.22(dd,1H),2.66(d,J=8.3Hz,1H),2.09–1.94( m,3H),1.83–1.62(m,6H),1.52(t,3H),1.45–1.20(m,8H),1.18(s,3H),1.08(d,J=13 .7Hz,2H),0.96(s,3H),0.90(d,J=6.6Hz,6H),0.85(s,3H),0.75(s,3H),0.65(s,3H). 13 C NMR(126MHz, CDCl3) δ175.6,153.3(d,J=248.2Hz),147.2,145.4(d,J=12.6Hz),1 45.0,130.1(d,J=3.8Hz),123.6,120.8(d,J=6.3Hz),115.9(d,J=17.6Hz),115.6 ,79.1,55.1,47.5,46.7,46.2,42.1,41.6,39.5,38.8,38.5,36.9,34.1,33.0,32.2,32.1,30.7,28.8,27.3,26.9,25.9,24.0,23.7,23.6,18.2,17.0,15.7,15.4. 19 F NMR (471MHz, CDCl3) δ-132.7.

[0196] Example 20

[0197] Example 20 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0198]

[0199] Its NMR data are as follows:

[0200] Green solid, yield 77.5%. 1H NMR (500MHz, CDCl3) δ9.50 (s, 1H), 8.21 (t, 2H), 8.08 (d, J = 8.7Hz, 1H), 7.98 (d, J = 8.3Hz, 1H), 7.73 (d, J = 6. 7Hz,1H),7.64(t,J=7.7Hz,1H),7.47(t,J=8.1Hz,1H),5.49(t,J=3.8Hz,1H),3.15(dd,J=11.3,4.6Hz,1H) ,2.63(d,J=8.5Hz,1H),2.05–1.90(m,3H),1.85–1.57(m,6H),1.55–1.50(m,3H),1.42–1.13(m,8H),1.13( s,3H),1.04(d,J=13.8Hz,2H),0.91(s,3H),0.88(d,J=6.0Hz,6H),0.79(s,3H),0.68(s,3H),0.66(s,3H). 13 CNMR (126MHz, CDCl3) δ175.0,153.4,147.7,147.3,145.0,136.4,129.8,129.1,128.4,127.7,127.2,123.7,118.7,78.7,55.0,47.5,46.6 ,46.5,42.0,41.8,39.4,38.7,38.4,36.9,34.0,32.9,32.1,32.1,30 .6,28.1,27.2,27.1,25.8,24.1,23.6,23.6,18.1,16.9,15.6,15.3.

[0201] Example 21

[0202] Example 21 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0203]

[0204] Its NMR data are as follows:

[0205] White solid, yield 81.4%. 1H NMR (500MHz, CDCl3) δ8.99(s,1H),8.03(s,1H),7.61(d,J=8.1Hz,2H),7.18(d,J=8.2 Hz,2H),5.54(t,J=3.8Hz,1H),3.20(dd,1H),2.62(d,J=8.5Hz,1H),2.36(s,3H),2.0 7–1.97(m,3H),1.89–1.64(m,6H),1.54(d,2H),1.47–1.23(m,8H),1.19(s,3H),1.08 (d,J=13.9Hz,2H),0.97(s,3H),0.92(s,6H),0.88(s,3H),0.75(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ174.8,147.8,145.6,140.8,131.1,129.5,127.8,123.6,79.0,55.2,47.6,46.8,46.5,42.3,42.2 ,39.6,38.8,38.6,37.0,34.1,33.1,32.2,30.8,28.2,27.3,27.2,25.9,24.2,23.8,23.7,21.6,18.3,17.1,15.6,15.5.

[0206] Example 22

[0207] Example 22 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 1.

[0208]

[0209] Its NMR data are as follows:

[0210] White solid, yield 64%. 1H NMR (500MHz, CDCl3) δ10.82(s,1H),8.97(s,1H),8.33(s,1H),7.02–6.98(m,1H),6.94 –6.88(m,2H),5.56(t,J=3.6Hz,1H),3.21(dd,J=11.4,4.2Hz,1H),2.62(d,J=8.8Hz,1H ),2.11–1.98(m,3H),1.83–1.64(m,6H),1.57(t,3H),1.49–1.25(m,8),1.20(s,3H),1. 11(d,J=13.7Hz,2H),0.98(s,3H),0.93(s,6H),0.90(s,3H),0.77(s,3H),0.73(s,3H). 13 C NMR (126MHz, CDCl3) δ174.9, 155.8 (d, J = 239.4Hz), 150.1, 145.4, 124.1, 118. 9,118.7,118.4(d,J=8.8Hz),117.7(d,J=8.8Hz),116.1(d,J=23.9Hz),79.1, 55.2,47.6,46.8,46.7,42.3,41.9,39.6,38.9,38.6,37.1,34.1,33.0,32.3,32.2,30.9,28.2,27.4,27.3,26.0,24.4,23.8,23.7,18.3,17.0,15.7,15.5. 19 F NMR (471MHz, CDCl3) δ-125.5.

[0211] Example 23

[0212] Example 23 provides an oleanolic acid derivative, the reaction equation of which is as follows, and the preparation steps are as follows:

[0213]

[0214] (1) Weigh 4.56 g (10 mmol) of oleanolic acid accurately using a balance of 0.01 g and pour it into a 250 mL round-bottom flask. Then, use a 50 mL syringe to repeatedly draw ultra-dry dichloromethane and add it to the round-bottom flask while stirring at room temperature. Transfer the reaction system to an ice bath and stir for 5 min. Weigh 2.5 mL of oxaloyl chloride accurately using a 5 mL syringe and add it dropwise to the round-bottom flask under an ice bath. After the addition is complete, stir for 10 min. Then, add 3 drops of N,N-dimethylformamide and then transfer to room temperature and stir for 8 h to obtain compound II.

[0215] (2) 4.74 g (10 mmol) of compound II was dried using an oil pump (2 mL of ultra-dry dichloromethane was added several times during the process to dissolve the compound before drying). 25 mL of dry dichloromethane was added. 5.16 mL (100 mmol) of 85% hydrazine hydrate was added to a 250 mL round-bottom flask using a 10 mL disposable syringe. 100 mL of tetrahydrofuran was accurately measured and mixed with 85% hydrazine hydrate using a graduated cylinder. The mixture was stirred at -20 °C for 30 min. Then, compound II was added dropwise to the 85% hydrazine hydrate solution using a 20 mL syringe. The mixture was reacted at -20 °C for 8 h. After the reaction was complete, the solvent was removed from the reaction solution under vacuum. After quenching with water, 3 x 50 mL of ethyl acetate was added for extraction three times. The organic phases were combined and washed successively with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed under vacuum to obtain compound III.

[0216] (3) Weigh 188 mg (0.3 mmol) of compound III into a 10 mL reaction tube using a 0.01 g balance. After dissolving, heat the tube to 0 °C, add p-fluorobenzyl bromide dropwise, stir for 5 min in an ice bath, then add triethylamine dropwise, and stir at room temperature for 6 h. After the reaction is complete, quench the reaction solution with water, extract three times with ethyl acetate, and then dry the organic phase with saturated brine and anhydrous sodium sulfate before column chromatography to obtain the oleanolic acid derivative (white solid, yield 77.2%).

[0217] The NMR data of oleanolic acid derivatives are as follows:

[0218] 1 H NMR (500MHz, CDCl3) δ9.13(s,1H),8.24(s,1H),7.83(d,J=8.2Hz,3H),7.63(d,J=8.5Hz ,3H),5.55(t,J=3.6Hz,1H),3.21(dd,J=11.3,4.3Hz,1H),2.63(d,J=10.6Hz,1H),2.11 –1.98(m,3H),1.88–1.64(m,6H),1.59–1.52(m,3H),1.48–1.22(m,8H),1.20(s,3H),1. 11(d,J=13.9Hz,2H),0.98(s,3H),0.93(s,6H),0.89(s,3H),0.76(s,3H),0.73(s,3H). 13C NMR (126MHz, CDCl3) δ 178.0, 162.4 (d, J = 247.0 Hz), 144.5, 133.4 (d, J = 3.8 Hz), 130.8 (d, J = 7.6 Hz), 123.36, 115.4 (d, J = 21.4 Hz), 79.0, 55.2, 55.2, 47.6, 46.5, 45.9, 42.0, 41.5, 39.5, 38.8, 38.6, 37.0, 34.1, 33.0, 32.5, 32.5, 30.8, 28.2, 27.3, 27.2, 25.9, 25.2, 23.7, 23.5, 23.5, 18.4, 17.2, 15.7, 15.4. Example 24

[0219] Example 24 provides an oleanolic acid derivative with the following structural formula. The preparation method is the same as in Example 23, except that the raw material in step (3) is p-nitrobenzyl bromide.

[0220]

[0221] Its NMR data are as follows:

[0222] Pale yellow solid, yield 48.2%. 1 H NMR (500MHz, CDCl3) δ8.17(d,J=8.7Hz,2H),7.51(d,J=8.8Hz,2H),7.37(s,1H),5.26(t,J =3.7Hz,1H),4.03(dd,1H),3.18(dd,J=11.2,4.6Hz,1H),2.39(d,J=7.7Hz,1H),1.99–1.82 (m,3H),1.74–1.58(m,6H),1.51(t,J=9.2Hz,3H),1.46–1.16(m,8H),1.12(s,3H),1.03(d, J=13.9Hz,2H),0.96(s,3H),0.87(d,J=7.7Hz,6H),0.84(s,3H),0.75(s,3H),0.70(s,3H). 13 C NMR (126MHz, CDCl3) δ178.5,147.5,145.5,144.5,129.6,123.7,123.4,78.9,55.2,47.5,46.4,46.0,42.0,41.5,39 .4,38.8,38.5,37.0,34.0,33.0,32.6,32.4,30.7,28.2,27.3,27.2,25.8,23.7,23.5,23.5,18.3,17.2,15.7,15.4.

[0223] Example 25

[0224] Example 25 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0225]

[0226] Its NMR data are as follows:

[0227] White solid, yield 61%. 1 H NMR (500MHz, CDCl3) δ8.54(d,J=6.1Hz,2H),7.37(s,1H),7.27(d,J=6.1Hz,2H),5.24(t,J= 3.7Hz,1H),3.93(dd,J=13.5,13.5Hz,2H),3.18(dd,J=11.1,4.8Hz,1H),2.37(d,J=8.6Hz,1 H),1.98–1.82(m,3H),1.73–1.56(m,6H),1.51–1.45(m,3H),1.43–1.16(m,8H),1.12(s,3H ),1.03(d,J=13.7Hz,2H),0.96(s,3H),0.87(s,6H),0.84(s,3H),0.76(s,3H),0.71(s,3H). 13 C NMR (126MHz, CDCl3) δ178.3,149.9,147.0,144.5,123.7,123.4,78.8,55.2,54.7,47.6,46.4,45.9,42.0,41.5,39. 4,38.8,38.6,37.0,34.0,33.0,32.5,32.4,30.7,28.2,27.3,27.2,25.7,23.7,23.5,23.5,18.3,17.2,15.7,15.4.

[0228] Example 26

[0229] Example 26 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0230]

[0231] Its NMR data are as follows:

[0232] White solid, yield 94%. 1H NMR(500MHz, CDCl3)δ7.34(s,1H),7.19(t,1H),7.11–7.04(m,1H),5.26(t,J= 3.7Hz,1H),3.84(dd,2H),3.19(dd,1H),2.39(d,J=7.9Hz,1H),2.00–1.84(m,3 H),1.75–1.58(m,6H),1.51(q,3H),1.46–1.20(m,8H),1.13(s,3H),1.03(d,J= 13.8Hz,2H),0.97(s,3H),0.89(s,6H),0.86(s,3H),0.76(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ178.2, 151.1 (dd, J1=12.6Hz, J2=58.0Hz), 149.1 (dd, J1=12.6Hz, J2=58. 0Hz), 144.5, 149.1 (t, J = 5.0Hz), 125.0 (dd, J1 = 3.8Hz, J2 = 6.3Hz), 123.4, 117.9 (d, J = 16.4Hz) ,117.2(d,J=17.6Hz),79.0,55.2,55.0,47.6,46.5,46.0,42.1,41.5,39.5,38.9,38.6,37.0, 34.1,33.0,32.6,32.5,30.8,28.2,27.3,27.3,25.8,23.8,23.6,23.5,18.4,17.2,15.7,15.4. 19 F NMR (471MHz, CDCl3) δ-137.8 (d, J = 23.55Hz), -139.6 (d, J = 23.55Hz).

[0233] Example 27

[0234] Example 27 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0235]

[0236] Its NMR data are as follows:

[0237] White solid, yield 46.8%. 1H NMR (500MHz, CDCl3) δ7.60(d,J=8.3Hz,2H),7.46(d,J=8.2Hz,2H),7.35(s,1H),5.25(t ,J=3.7Hz,1H),3.95(dd,2H),3.18(dd,J=11.2,4.6Hz,1H),2.37(d,J=7.7Hz,1H),1.99– 1.81(m,3H),1.73–1.57(m,6H),1.49(q,3H),1.43–1.16(m,8H),1.12(s,3H),1.02(d,J= 13.8Hz,2H),0.96(s,3H),0.87(d,J=5.2Hz,6H),0.84(s,3H),0.75(s,3H),0.70(s,3H). 13 C NMR (126MHz, CDCl3) δ178.4,144.5,143.4,132.3,129.6,123.4,118.9,111.4,78.9,55.5,55.2,47.6,46.4,46.0,42.0,41 .5,39.5,38.8,38.6,37.0,34.0,33.0,32.5,32.4,30.7,28.2,27.3,27.2,25.8,23.7,23.6,23.5,18.3,17.2,15.7,15.4.

[0238] Example 28

[0239] Example 28 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0240]

[0241] Its NMR data are as follows:

[0242] White solid, yield 25.7%. 1H NMR (500MHz, CDCl3) δ7.32 (s, 1H), 7.27 (d, J = 8.7Hz, 2H), 6.86 (d, J = 8.8Hz, 2H), 5.23 (t, J = 3. 7Hz,1H),3.84(dd,J=11.7,11.7Hz,2H),3.79(s,3H),3.19(dd,J=11.2,4.6Hz,1H),2.40(d,J =7.7Hz,1H),1.98–1.83(m,3H),1.72–1.58(m,6H),1.52(q,3H),1.45–1.18(m,8H),1.13(s,3 H),1.03(d,J=13.8Hz,2H),0.97(s,3H),0.89(s,3H),0.87(s,6H),0.76(s,3H),0.72(s,3H). 13 C NMR (126MHz, CDCl3) δ177.6,159.1,144.4,130.4,129.7,123.3,113.9,78.9,55.4,55.3,55.2,47.6,46.5,45.8,42.0,41 .5,39.4,38.8,38.6,37.0,34.1,33.0,32.5,32.4,30.7,28.2,27.3,27.2,25.8,23.7,23.5,23.5,18.3,17.1,15.7,15.4.

[0243] Example 29

[0244] Example 29 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0245]

[0246] Its NMR data are as follows:

[0247] White solid, yield 74%. 1H NMR (500MHz, CDCl3) δ7.38(s,1H),7.23(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),5.21(t, J=3.7Hz,1H),3.84(dd,2H),3.18(dd,J=11.1,4.6Hz,1H),2.41(d,J=7.9Hz,1H),2.33(s, 3H),1.98–1.81(m,3H),1.74–1.56(m,6H),1.52(q,3H),1.45–1.17(m,8H),1.12(s,3H), 1.02(d,J=13.8Hz,2H),0.97(s,3H),0.89(s,3H),0.87(s,6H),0.76(s,3H),0.71(s,3H). 13 C NMR (126MHz, CDCl3) δ177.5,144.3,137.2,134.4,129.2,129.1,123.3,78.8,55.7,55.2,47.6,46.4,45.8,41.9,41.4,39 .4,38.8,38.5,36.9,34.1,33.0,32.5,32.4,30.7,28.1,27.3,27.2,25.7,23.6,23.5,23.4,21.2,18.3,17.1,15.7,15.4.

[0248] Example 30

[0249] Example 30 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0250]

[0251] Its NMR data are as follows:

[0252] White solid, yield 73%. 1H NMR(500MHz, CDCl3)δ7.32(s,1H),7.18(d,J=7.5Hz,1H),7.15–7.12(m,1H),6.95(t,1H),5.25(t, J=3.6Hz,2H),3.84(dd,J=11.9,11.9Hz,2H),3.20(dd,J=11.3,4.6Hz,1H),2.40(d,J=8.8Hz,1H), 2.26(s,3H),2.01–1.84(m,3H),1.74–1.58(m,6H),1.53(q,3H),1.49–1.20(m,8H),1.14(s,3H),1 .04(d,J=13.8Hz,2H),0.98(s,3H),0.90(s,3H),0.88(d,J=2.6Hz,6H),0.77(s,3H),0.73(s,3H). 13 C NMR (126MHz, CDCl3) δ177.9, 160.9 (d, J = 245.7Hz), 144.52, 133.0 (d, J = 3.8Hz), 132.3 (d,J=5.0Hz),128.0(d,J=8.8Hz),124.8(d,J=17.6Hz),123.3,115.0(d,J=22.7Hz),7 9.0,55.3,55.2,47.6,46.5,45.9,42.0,41.5,39.5,38.8,38.6,37.0,34.1,33.0,32.5,32.4,30.8,28.2,27.3,27.2,25.8,23.7,23.5,18.4,17.2,15.7,15.4,14.6,14.6. 19 F NMR (471MHz, CDCl3) δ-119.4.

[0253] Example 31

[0254] Example 31 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 23.

[0255]

[0256] Its NMR data are as follows:

[0257] White solid, yield 94%. 1H NMR (500MHz, CDCl3) δ7.97(d,1H),7.54(dd,J=14.3,7.0Hz,2H),7.43(t,J=7.7Hz,1H),7 .36(s,1H),5.31(t,1H),4.24(dd,J=71.3,14.2Hz,2H),3.20(dd,1H),2.39(d,J=9.3Hz, 1H),1.93–1.86(m,3H),1.73–1.58(m,6H),1.51(q,3H),1.44–1.24(m,8H),1.11(s,3H), 1.01(d,2H),0.97(s,3H),0.88(d,J=6.4Hz,6H),0.85(s,3H),0.77(s,3H),0.70(s,3H). 13 C NMR (126MHz, CDCl3) δ178.2,149.4,144.6,133.4,132.9,131.9,128.6,125.1,123.6,79.0,55.2,53.4,47.6,46.4,45.7,42.0 ,41.5,39.5,38.9,38.6,37.0,34.1,33.0,32.4,32.3,30.8,28.2,27.3,27.2,25.8,23.7,23.6,23.6,18.4,17.0,15.7,15.5.

[0258] Example 32

[0259] This example provides an oleanolic acid derivative, the reaction equation of which is as follows, and the preparation steps are as follows:

[0260]

[0261] Accurately weigh 4.5671 g (10 mmol) of oleanolic acid using a 0.01% balance and pour it into a 250 mL round-bottom flask. Then, using a 50 mL syringe, repeatedly add ultra-dry dichloromethane to the round-bottom flask and stir to dissolve it at room temperature. Accurately weigh 3.7831 g (100 mmol) of sodium borohydride into a 250 mL round-bottom flask and 8.8834 g (35 mmol) of elemental iodine into a 50 mL round-bottom flask. Using a 50 mL syringe, add 25 mL of tetrahydrofuran to the round-bottom flask containing the elemental iodine. Dissolve the tetrahydrofuran by stirring at room temperature; use a 50mL syringe to repeatedly add 100mL of tetrahydrofuran to a round-bottom flask containing sodium borohydride, stir at room temperature for 10 minutes, then transfer to an ice bath for stirring; use a 50mL syringe to slowly add the dissolved iodine solution dropwise to the round-bottom flask containing sodium borohydride under an ice bath, stir for 10 minutes after the addition is complete, then transfer to 40℃ and stir for 30 minutes; use a 50mL syringe to slowly add the dissolved oleanolic acid solution dropwise to the round-bottom flask containing iodine and sodium borohydride, stir overnight at 40℃ to obtain compound ②;

[0262] 5.97 g (13.5 mmol) of compound ② was dissolved in dichloromethane. 0.1649 g (1.35 mmol) of 4-dimethylaminopyridine was weighed precisely using a 0.01 mL balance. 10.1 mL (108 mmol) of acetic anhydride, 18.8 mL (135 mmol) of triethylamine, and 100 mL of dichloromethane were repeatedly added to a 250 mL round-bottom flask using a 10 mL syringe and stirred at room temperature for 10 min. The dissolved intermediate of formula (II) was added to the system containing 4-dimethylaminopyridine and stirred overnight to obtain compound ③.

[0263] 5.7861 g (11 mmol) of compound ③ was placed in a 250 mL round-bottom flask. Tetrahydrofuran was added to the flask repeatedly using a 20 mL syringe and stirred at 0 °C until dissolved. 0.6172 g (11 mmol) of potassium hydroxide was accurately weighed using a 0.01 mL balance and added to a 50 mL round-bottom flask. 30 mL of methanol was added to the 50 mL flask using a 20 mL syringe and stirred vigorously to dissolve the potassium hydroxide. The dissolved potassium hydroxide solution was added dropwise to the intermediate solution of formula (III) under ice bath conditions. The reaction was monitored by TLC every half hour. After the reaction was completed, the reaction solution was diluted and quenched with water. After extraction with ethyl acetate three times, the organic phase was dried over saturated brine and anhydrous sodium sulfate, and then subjected to column chromatography to obtain compound IV.

[0264] 2.74 g (5.6 mmol) of compound IV was added to a 100 mL round-bottom flask. 3.6 g (8.4 mmol) of Des Martin reagent was accurately weighed using a 0.01 g balance and added to the flask. 50 mL of dichloromethane was added using a 50 mL syringe. The flask was placed in an ice bath and stirred for 6 h. After the reaction was complete, 50 mL of dichloromethane was added to dilute the mixture. The reaction system was washed with a 1:1 volume mixture of saturated sodium bicarbonate and saturated sodium bisulfite. After washing five times, saturated sodium chloride was added, and the mixture was dried over anhydrous sodium sulfate. The solution was then subjected to column chromatography to obtain compound V.

[0265] 144.7 mg (0.3 mmol) of compound V was added to a 10 mL reaction tube. 47.7 g (0.35 mmol) of 3,4-dimethoxybenzoylhydrazine was added to the reaction tube precisely using a 0.01 g balance. 4 mL of ethanol was added to the mixture using a 5 mL syringe, and the mixture was stirred at 70 °C for 8 h. After the reaction was complete, the mixture was quenched with water, extracted twice with dichloromethane, dried over saturated sodium chloride and anhydrous sodium sulfate, and then subjected to column chromatography. Recrystallization by acetonitrile yielded a white solid (88.1% yield), which was presented as an indivisible diastereomeric mixture, Dr 11:1.

[0266] The NMR data of oleanolic acid derivatives are as follows:

[0267] 1 H NMR(500MHz,DMSO-d6)δ11.15(s,1H),7.59(s,1H),7.48(d,J=8.7Hz,1H),7.42(s,1H) ,7.03(d,J=8.5Hz,1H),5.22(s,1H),4.38(dd,J=11.7,4.5Hz,1H),3.81(s,6H),2.36( d,J=10.1Hz,1H),2.08–1.93(m,8H),1.55–1.23(m,12H),1.17–1.07(m,6H),0.98(q,J =11.9Hz,2H),0.90(d,J=3.7Hz,6H),0.86(s,3H),0.80(d,J=7.3Hz,6H),0.71(s,3H). 13C NMR(126MHz,DMSO-d6)δ170.1 162.0,159.0 151.5,148.3 144.0 125.6,122.0,120.8,110.9,110.8,79.955.6,54.5,46.8,45.4,43.8,41.1,37.5,37.2,36.4,33. 3,32.9,32.5,32.1,30.4,27.7,26.1,25.9,23.5,23.3,23.2,23.0,21.0,17.7,16.8,16.6,15.0.

[0268] Example 33

[0269] Example 33 provides an oleanolic acid derivative with the following structural formula. The preparation method is the same as in Example 32. As an indivisible diastereomeric mixture, Dr 10:2.3.

[0270]

[0271] Its NMR data are as follows:

[0272] White solid, yield 71.7%. 1 H NMR (500MHz, DMSO-d6) δ11.37(s,1H),11.23(s,0.23H),7.85(d,J=8.6Hz,2H),7.78(d,J=8.1Hz,0.46H),7.5 7(t,3H),7.46(d,J=7.3Hz,0.46H),7.18(s,0.23H),5.23(t,J=3.9Hz,1H),5.04(s,0.23H),4.38(dd,1.23H), 2.36(dd,J=13.8,4.5Hz,1H),2.09–1.73(m,9.84H),1.58–1.30(m,14.76H),1.15(q,J=18.5Hz,7.38H),0.99( t,2.46H),0.90(d,J=4.4Hz,7.38H),0.86(s,3.69H),0.80(d,J=7.0Hz,7.38H),0.72(s,3H),0.54(s,0.69H). 13C NMR(126MHz,DMSO-d6)δ170.6,161.9,160.5144.3,136.8,132.8,132.0,129.9,128.9,127.8,122.6,80.3,55.0,47.3,45.9, 44.2,41.6,38.0,37.7,36.9,33.8,33.4,32.9,32.5,30.9,28.2,26.5,26.3,23.9,23.7,23.5,21.4,18.2,17.2,17.1,15.5.

[0273] Example 34

[0274] Example 34 provides an oleanolic acid derivative; (3S, 4aR, 6aR, 6bS, 8aS, 12aS, 14aR, 14bR)-4,4,6a,6b,11,11,14b-heptamethyl-8a-((E)-(2-(4-nitrobenzoyl)hydrazine)methyl)-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-docosahexaeno-3-yl acetate, Dr 10:2.3, as an indivisible diastereomeric mixture. Its structural formula is as follows, and the preparation method is as described in Example 32, as an indivisible diastereomeric mixture, Dr 10:2.3.

[0275]

[0276] Its NMR data are as follows: yellow solid, yield 69.1%. 1 H NMR (500MHz, DMSO-d6) δ11.37(s,1H),11.23(s,0.23H),7.78(d,J=8.6Hz,2H),7.70(d,J=8.6Hz,2.6H),7.60(d, J=9.8Hz,1.46H),7.18(s,0.23H),5.23(t,J=3.9Hz,1H),5.03(s,0.23H),4.38(dd,J=11.7,4.4Hz,1.23H),2.36 (dd,J=13.5,4.9Hz,1H),2.09–1.67(m,9.84H),1.55–1.23(m,14.76H),1.10(q,J=32.2Hz,7.38H),1.01(t,J=13 .9Hz, 2.46H), 0.90 (t, J = 4.5Hz, 7.38H), 0.86 (s, 3.69H), 0.80 (d, J = 6.9Hz, 7.38H), 0.72 (s, 3H), 0.52 (s, 0.69H). 13C NMR (126MHz, DMSO-d6) δ170.0,167.0,160.9,155.8,149.1,148.2,143.8,143.6,140.6,139.3,13 0.6,129.0,123.5,122.4,122.1,121.5,79.8,54.5,54.5,46.8,46.8,45.6,45.4,43.7,41.5,41.1 ,41.0,37.6,37.2,36.4,36.3,33.4,33.3,32.9,32.8,32.3,32.1,31.3,30.4,29.3,29.1,27.7,26.3,26.1,25.8,25.5,24.0,23.4,23.2,23.0,22.7,22.1,20.9,17.7,16.8,16.7,16.6,15.0,14.9.

[0277] Example 35

[0278] Example 35 provides an oleanolic acid derivative, (3S,4aR,6aR,6bS,8aS,12aS,14aR,14bR)-8a-((E)-(2-(4-fluorobenzoyl)hydrazine)methyl)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-docosahexahydrolimonene-3-ylacetate. Dr 10:2.2, as an indivisible diastereomeric mixture. Its structural formula is as follows, and the preparation method is as described in Example 32, as an indivisible diastereomeric mixture, Dr 10:2.2.

[0279]

[0280] Its NMR data are as follows: white solid, yield 77.9%. 1H NMR(500MHz,DMSO-d6)δ11.33(s,1H),11.17(s,0.22H),7.92–7.87(m,2.44H),7.59(s,1H),7.32(t,J =8.8Hz,2H),7.21(q,0.66H),5.23(t,J=3.9Hz,1H),5.07(s,0.22H),4.38(dd,1.22H),2.36(dd,J=13 .8,4.4Hz,1H),2.06–1.76(m,9.76H),1.55–1.25(m,14.64H),1.10(q,J=28.1Hz,7.32H),0.99(t,2.4 4H), 0.90 (t, J = 4.1Hz, 7.32H), 0.86 (d, 3.66H), 0.80 (d, J = 7.32Hz, 8H), 0.72 (s, 3H), 0.56 (s, 0.66H). 13 C NMR(126MHz, DMSO-d6)δ170.1,164.0(d,J=249.5Hz),161.5,159.7,143.9,130.1(d,J=11.3Hz),130.0,122.1,115.3(d,J=22.5Hz),79.9,54 .5,46.8,45.4,43.8,41.1,37.5,37.2,36.4,33.3,32.9,32.4,32.1,3 0.4,27.7,26.1,25.8,23.5,23.2,23.0,21.0,17.7,16.8,16.6,15.0.

[0281] Example 36

[0282] Example 36 provides an oleanolic acid derivative, (3S,4aR,6aR,6bS,8aS,12aS,14aR,14bR)-8a-((E)-(2-(3-fluorobenzoyl)hydrazine)methyl)-4,4,6a,6b,11,11,14b-heptamethyl-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-docosahexaeno-3-ylacetate. Dr 10:2.2, as an indivisible diastereomeric mixture. Its structural formula is as follows, and the preparation method is as described in Example 32, as an indivisible diastereomeric mixture, Dr 10:2.2.

[0283]

[0284] Its NMR data are as follows:

[0285] White solid, yield 80.6%. 1 H NMR (500MHz, DMSO-d6) δ11.37(s,1H),11.27(s,0.22H),7.68(d,J=7.9Hz,1H),7.64–7.60(m,2H),7.54(td,J=8.1,5.9Hz,1.4 4H),7.45(t,J=6.2Hz,0.22H),7.41(td,J=8.0,2.3Hz,1H),7.35(t,J=8.3Hz,0.22H),7.19(s,0.22H),5.24(t,J=3.6Hz,1H),5 .00(s,0.22H),4.38(dd,J=11.8,4.2Hz,1.22H),2.37(dd,1H),2.09–1.70(s,9.76H),1.57–1.28(m,14.64H),1.14(q,7.32H), 0.98(t,J=16.2Hz,2.44H),0.90(t,J=4.2Hz,7.32H),0.87(d,3.67H),0.80(d,J=7.0Hz,7.32H),0.73(s,3H),0.56(s,0.66H). 13 C NMR (126MHz, DMSO-d6) δ170.1,161.9(d,J=245.7Hz),161.2(d,J=3.8Hz),160.2,14 3.9,135.9(d,J=6.3Hz),130.6(d,J=7.6Hz),123.7,122.1,118.4(d,J=21.4Hz),11 4.3(d,J=22.7Hz),79.9,54.5,46.8,45.4,43.7,41.1,37.5,37.2,36.4,33.3,32.9 ,32.4,32.1,30.4,27.7,26.1,25.8,23.5,23.2,23.0,20.9,17.7,16.8,16.6,15.0.

[0286] Example 37

[0287] This example provides an oleanolic acid derivative, the reaction equation of which is as follows, and the preparation steps are as follows:

[0288]

[0289] 144.7 mg (0.3 mmol) of compound V prepared in Example 32 was added to a 10 mL reaction tube. 0.35 mmol (47.7 g) of m-fluorobenzoyl hydrazine was added to the reaction tube using a 0.01 g balance. 4 mL of ethanol was added using a 5 mL syringe, and the mixture was stirred at 70 °C for 8 h. After the reaction was complete, the mixture was quenched with water, extracted twice with dichloromethane, and dried over saturated sodium chloride and anhydrous sodium sulfate to obtain compound VI.

[0290] Take 0.3 mmol of compound VI and place it in a 10 mL reaction tube. Accurately weigh 188.5 mg (3 mmol) of sodium cyanoborohydride using a 0.01 g balance and add it to the reaction tube. Use a 5 mL syringe to draw 3 mL of ultra-dry methanol and add 2 mL of ultra-dry dichloromethane. Stir for 3 h in an ice bath. After the reaction is complete, quench with water and extract three times with dichloromethane. After washing with saturated sodium chloride and drying with anhydrous sodium sulfate, column chromatography is used to obtain (white solid, yield 62.9%).

[0291] The NMR data for oleanolic acid derivatives are as follows:

[0292] 1 H NMR (500MHz, CDCl3) δ7.87 (s, 1H), 7.47 (dd, J = 13.4, 8.3Hz, 2H), 7.39 (td, J = 8.0, 5.5Hz, 1H), 7.19 (td, J = 8. 3,2.7Hz,1H),5.17(t,J=3.7Hz,1H),4.52–4.43(m,1H),3.02(d,J=11.7Hz,1H),2.51(d,J=11.7Hz,1H),2.0 3(s,3H),2.01–1.81(m,5H),1.73(t,J=13.5Hz,1H),1.62–1.57(m,4H),1.50(q,3H),1.42–1.18(m,7H),1.1 5(s,3H),1.03(d,J=13.7Hz,4H),0.92(s,3H),0.90(s,3H),0.88(d,J=4.3Hz,6H),0.86(s,3H),0.84(s,3H). 13CNMR (126MHz, CDCl3) δ171.2, 166.0, 162.9 (d, J = 248.2Hz), 144.5, 135.4 (d, J = 7.6Hz) ,130.5(d,J=7.6Hz),122.5,122.4(d,J=3.8Hz),118.9(d,J=20.2Hz),114.4(d,J=22. 7Hz),81.1,60.8,55.4,47.6,46.4,44.7,41.8,40.0,38.4,37.8,36.9,36.1,34.3,33 .4,32.6,32.6,31.1,28.2,26.1,25.8,23.7,23.7,22.7,21.5,18.3,16.8,16.8,15.7.

[0293] Example 38

[0294] Example 38 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0295]

[0296] Its NMR data are as follows:

[0297] Yellow solid, yield 30.1%. 1 H NMR (500MHz, CDCl3) δ8.27(d,J=8.8Hz,2H),7.91(d,J=8.9Hz,2H),5.17(t,J=3.6Hz,1H),4. 47(t,1H),3.04(d,J=11.6Hz,1H),2.52(d,J=11.6Hz,1H),2.03(s,3H),2.00–1.81(m,5H),1. 73(t,J=13.5Hz,1H),1.59(q,4H),1.53–1.47(m,3H),1.39–1.21(m,7H),1.15(s,3H),1.04( d,J=14.9Hz,4H),0.91(s,3H),0.90(s,3H),0.88(d,J=6.3Hz,6H),0.85(s,3H),0.84(s,3H). 13C NMR (126MHz, CDCl3) δ171.2,165.2,149.9,144.5,138.8,128.2,124.1,122.6,81.0,60.8,55.4,47.6,46.4,44.7,41.8,40 .0,38.4,37.8,36.9,36.1,34.3,33.3,32.6,32.6,31.1,28.2,26.1,25.8,23.7,23.7,22.7,21.5,18.3,16.9,16.8,15.7.

[0298] Example 39

[0299] Example 39 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0300]

[0301] Its NMR data are as follows:

[0302] White solid, yield 53.4%. 1 H NMR (500MHz, CDCl3) δ7.97 (s, 1H), 6.97 (s, 2H), 5.14 (t, J = 3.7Hz, 1H), 4.45 (dd, 1H), 3.84 (d, J=1.8Hz,9H),3.01(d,J=11.4Hz,1H),2.47(d,J=11.6Hz,1H),2.01(s,3H),1.97–1.78(m,5H), 1.72(d,J=13.6Hz,1H),1.58(q,4H),1.51–1.44(m,3H),1.40–1.17(m,7H),1.12(s,3H),1.01 (q,J=15.9Hz,4H),0.89(s,3H),0.86(d,J=3.7Hz,6H),0.85(s,3H),0.83(s,3H),0.82(s,3H). 13 C NMR (126MHz, CDCl3) δ171.1,166.9,153.3,144.5,141.1,128.4,122.3,104.3,81.0,61.0,60.7,56.3,55.3,47.5,46.3,44.7 ,41.7,39.8,38.3,37.7,36.8,35.9,34.3,33.3,32.6,32.4,31.0,28.1,26.0,25.7,23.7,23.6,22.5,21.4,18.2,16.8,15.6.

[0303] Example 40

[0304] Example 40 provides an oleanolic acid derivative with the following structural formula, and the preparation method is as described in Example 37.

[0305]

[0306] Its NMR data are as follows:

[0307] White solid, yield 31.6%. 1 H NMR (500MHz, CDCl3) δ7.69(d,J=8.8Hz,2H),6.90(d,J=8.8Hz,2H),5.16(t,J=3.7Hz,1H),4.48(t ,1H),3.83(s,3H),3.01(d,J=11.6Hz,1H),2.51(d,J=11.7Hz,1H),2.04(s,3H),2.00–1.81(m,5H ),1.74(t,J=13.5Hz,1H),1.63–1.57(m,4H),1.54–1.47(m,3H),1.34–1.22(m,7H),1.15(s,3H), 1.03(q,J=7.5Hz,4H),0.93(s,3H),0.91(s,3H),0.88(d,J=3.6Hz,6H),0.86(s,3H),0.84(s,3H). 13 C NMR (126MHz, CDCl3) δ171.2,166.9,162.4,144.5,128.7,125.4,122.4,113.9,81.0,60.9,55.5,55.3,47.6,46.4,44.7,41 .8,39.9,38.4,37.8,36.9,36.0,34.3,33.3,32.6,32.5,31.0,29.8,28.1,26.1,25.8,23.7,23.6,21.4,16.8,16.8,15.6.

[0308] Example 41

[0309] Example 41 provides an oleanolic acid derivative with the following structural formula, and the preparation method is as described in Example 37.

[0310]

[0311] Its NMR data are as follows:

[0312] White solid, yield 94%. 1H NMR (500MHz, CDCl3) δ8.15 (s, 1H), 7.87 (d, J = 8.2Hz, 2H), 7.68 (d, J = 8.5Hz, 2H), 5.16 (t, J = 3. 7Hz,1H),4.47(t,J=8.0Hz,1H),3.02(d,J=11.6Hz,1H),2.51(d,J=11.7Hz,1H),2.03(s,3H),2 .00–1.80(m,5H),1.74(t,J=13.5Hz,1H),1.61–1.56(m,4H),1.46(q,J=9.5Hz,3H),1.36–1.1 8(m,7H),1.14(s,3H),1.06–0.97(m,4H),0.88(s,9H),0.87(s,3H),0.85(s,3H),0.83(s,3H). 13 C NMR (126MHz, CDCl3) δ171.1,165.8,144.3,136.3,133.4(q,J=32.8Hz),127.5,125.6(q,J=11.3Hz),123.6(q,J=273Hz),122.4,80.9,60.7,55.2,4 7.5,46.2,44.6,41.6,39.8,38.2,37.7,36.8,35.9,34.2,33.2,32.5,32. 4,30.9,28.0,26.0,25.7,23.6,23.5,23.5,22.5,21.3,18.2,16.6,15.5.

[0313] Example 42

[0314] Example 42 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0315]

[0316] Its NMR data are as follows:

[0317] White solid, yield 38.2%. 1H NMR (500MHz, CDCl3) δ8.05 (s, 1H), 7.61 (d, J = 8.7Hz, 2H), 7.54 (d, J = 8.6Hz, 2H), 5.15 (t, J = 3.7Hz, 1H),4.47(t,J=8.0Hz,1H),3.00(d,J=11.6Hz,1H),2.48(d,J=11.6Hz,1H),2.03(s,3H),1.98–1.79 (m,5H),1.72(t,J=13.5Hz,1H),1.61–1.55(m,4H),1.47(t,J=11.1Hz,3H),1.35–1.15(m,7H),1.1 3(s,3H),1.01(m,J=19.1Hz,4H),0.89(s,3H),0.88(s,6H),0.86(s,3H),0.85(s,3H),0.84(s,3H). 13 C NMR (126MHz, CDCl3) δ171.2,166.2,144.4,131.9,128.6,126.5,122.4,81.0,60.7,55.3,47.6,46.3,44.7,41.7,39.9, 38.3,37.8,36.9,36.0,34.3,33.3,32.6,32.4,31.0,28.1,26.1,25.8,23.7,23.6,22.5,21.4,18.3,16.8,16.7,15.6.

[0318] Example 43

[0319] Example 43 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0320]

[0321] Its NMR data are as follows:

[0322] White solid, yield 69.2%. 1H NMR (500MHz, CDCl3) δ8.37(s,1H),7.77(s,1H),7.56(d,J=6.0Hz,1H),7.24(d,J=8.0Hz,1H),5.13( t,J=3.8Hz,1H),4.45(t,1H),2.99(d,J=11.6Hz,1H),2.46(d,J=11.7Hz,1H),2.38(s,3H),2.02(s,3 H),1.96–1.78(m,5H),1.70(t,J=13.5Hz,1H),1.56(q,4H),1.43(q,J=10.5Hz,3H),1.31–1.15(m,7 H),1.11(s,3H),0.98(dd,J=47.0,12.3Hz,4H),0.86(s,6H),0.85(s,3H),0.84(s,6H),0.82(s,3H). 13 C NMR (126MHz, CDCl3) δ171.2,165.9,144.5,140.0,134.8,132.2,131.1,127.8,125.2,122.4,81.0,60.8,55.3,47.6,46.4,44.7,41. 7,39.9,38.3,37.8,36.9,36.0,34.3,33.3,32.6,32.4,31.0,28.1,26.1,25.8,23.7,23.6,22.5,21.4,20.3,18.3,16.8,16.7,15.6.

[0323] Example 44

[0324] Example 44 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0325]

[0326] Its NMR data are as follows:

[0327] White solid, yield 54.2%. 1H NMR(500MHz, CDCl3) δ7.56(d,J=8.7Hz,1H),6.83(d,J=8.7Hz,1H),5.15(t,J=3.8Hz,1H),4.47 (t,J=8.0Hz,1H),3.01(d,J=11.6Hz,1H),2.50(d,J=11.7Hz,1H),2.04(s,3H),1.98–1.80(m,5 H),1.73(t,J=13.6Hz,1H),1.58(q,J=11.0Hz,4H),1.48(q,J=15.3Hz,3H),1.32–1.18(m,7H), 1.13(s,3H),1.05–0.95(m,4H),0.89(s,3H),0.87(s,6H),0.85(d,J=2.9Hz,6H),0.83(s,3H). 13 C NMR (126MHz, CDCl3) δ171.4,167.5,159.8,144.5,128.9,124.7,122.5,115.8,81.2,60.9,55.4,47.6,46.4,44.7,41.8 ,40.0,38.4,37.8,36.9,36.0,34.3,33.4,32.6,32.5,31.1,28.2,26.1,25.8,23.8,23.7,22.7,21.5,18.3,16.8,15.7.

[0328] Example 45

[0329] Example 45 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0330]

[0331] Its NMR data are as follows:

[0332] White solid, yield 35.5%. 1H NMR (500MHz, CDCl3) δ7.76(s,1H),7.36(d,J=2.0Hz,1H),7.24(dd,J=8.3,2.0Hz,1H),6.84(d,J=8.5Hz,1H ),5.15(t,J=3.7Hz,1H),4.47(t,1H),3.90(s,6H),3.02(d,J=11.4Hz,1H),2.50(d,J=11.7Hz,1H),2.03(s ,3H),1.99–1.80(m,5H),1.74(d,J=13.5Hz,1H),1.62–1.56(m,4H),1.52–1.46(m,3H),1.40–1.19(m,7H), 1.14(s,3H),1.06–0.95(m,4H),0.91(s,3H),0.89(s,3H),0.87(d,J=3.8Hz,6H),0.85(s,3H),0.83(s,3H). 13 C NMR (126MHz, CDCl3) δ171.2,167.0,152.0,149.2,144.6,125.8,122.4,119.4,110.5,81.0,60.8,56.1,55.3,47.6,46.4,44.7,4 1.8,39.9,38.4,37.8,36.9,36.0,34.3,33.3,32.6,32.5,31.1,28.1,26.1,25.8,23.7,23.7,22.7,21.4,18.3,16.8,16.8,15.6.

[0333] Example 46

[0334] Example 46 provides an oleanolic acid derivative with the following structural formula, and the preparation method is as described in Example 37.

[0335]

[0336] Its NMR data are as follows:

[0337] White solid, yield 86.3%. 1H NMR (500MHz, CDCl3) δ7.74(d,J=7.0Hz,2H),7.46(t,J=7.4Hz,1H),7.38(t,J=7.6Hz,2H),5.13(t,J= 3.7Hz,1H),4.45(t,J=8.0Hz,1H),3.01(d,J=11.6Hz,1H),2.49(d,J=11.7Hz,1H),2.01(s,3H),1.97 –1.78(m,5H),1.71(t,J=13.5Hz,1H),1.60–1.54(m,4H),1.48(q,3H),1.32–1.16(m,7H),1.12(s,3H ),1.00(q,J=12.0Hz,4H),0.88(s,3H),0.86(d,J=2.7Hz,6H),0.85(s,3H),0.83(s,3H),0.82(s,3H). 13 CNMR (126MHz, CDCl3) δ171.1,167.1,144.5,133.1,131.7,128.6,127.0,122.4,81.0,60.8,55.3,47.6,46.4,44.7,41.7,3 9.9,38.3,37.8,36.8,35.9,34.3,33.3,32.6,32.5,31.0,28.1,26.1,25.8,23.7,23.6,22.5,21.4,18.3,16.8,16.7,15.6.

[0338] Example 47

[0339] Example 47 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0340]

[0341] Its NMR data are as follows:

[0342] White solid, yield 80.5%. 1H NMR (500MHz, CDCl3) δ8.46(s,1H),7.86(d,J=8.6Hz,2H),7.69(d,J=8.6Hz,2H),5.13(t,J=3.8 Hz,1H),4.43(t,J=8.0Hz,1H),2.98(d,J=11.6Hz,1H),2.46(d,J=11.7Hz,1H),2.00(s,3H),1.9 5–1.76(m,5H),1.71(t,J=13.5Hz,1H),1.56(q,4H),1.46(d,J=10.3Hz,3H),1.32–1.15(m,7H), 1.11(s,3H),0.98(q,J=14.4Hz,4H),0.85(d,J=3.8Hz,9H),0.83(d,J=3.5Hz,6H),0.81(s,3H). 13 C NMR (126MHz, CDCl3) δ171.2,165.3,144.4,137.0,132.5,127.7,122.5,118.0,115.3,81.0,60.7,55.3,47.5,46.3,44.6,4 1.7,39.9,38.3,37.8,36.9,36.0,34.2,33.3,32.6,32.5,31.0,28.1,26.1,25.7,23.7,23.6,22.6,21.4,18.3,16.8,15.6.

[0343] Example 48

[0344] Example 48 provides an oleanolic acid derivative with the following structural formula, and the preparation method is the same as in Example 37.

[0345]

[0346] Its NMR data are as follows:

[0347] White solid, yield 71.7%. 1H NMR(500MHz, CDCl3) δ7.83(s,1H),7.74(dd,J=8.8,5.2Hz,2H),7.09(t,J=8.6Hz,2H),5.16(t,J= 3.7Hz,1H),4.48(t,1H),3.02(d,J=11.6Hz,1H),2.50(d,J=11.7Hz,1H),2.03(s,3H),2.00–1.81 (m,5H),1.73(t,J=13.5Hz,1H),1.62–1.57(m,4H),1.51(q,J=8.7Hz,3H),1.34–1.21(m,7H),1.1 5(s,3H),1.02(q,4H),0.92(s,3H),0.90(s,3H),0.88(d,J=4.9Hz,6H),0.86(s,3H),0.84(s,3H). 13 C NMR (126MHz, CDCl3) δ171.2,166.3,164.6(d,J=168.8Hz),144.5,129.3,129.3,122.4,115.8(d,J=21.4Hz),81.0,60.8,55.3,47.6 ,46.4,44.7,41.8,39.9,38.4,37.8,36.9,36.0,34.3,33.3,32.6,32.5,31.0,28.1,26.1,25.8,23.7,23.6,22.6,18.3,16.8,15.6.

[0348] Performance testing

[0349] The oleanolic acid derivatives prepared above were tested for their activity against influenza A (H1N1) virus. The specific testing method is as follows:

[0350] 1. Experimental instruments and materials

[0351] 31-Multifunctional microplate reader, SPARK10M full-grating type, PerkinElmer;

[0352] Clean bench;

[0353] Bond A3Pipette manual single-channel adjustable pipette, 0.5-10uL, 10-100uL, 100-1000uL Titan Technology;

[0354] 96-well plate (transparent), flat bottom, nice;

[0355] Influenza virus infection CPE, purchased from A / PR / 8(PR);

[0356] Positive control drug: Oseltamivir carboxlate (OSC), Shanghai Hekang Biotechnology Co., Ltd.

[0357] 2. Experimental Methods

[0358] The anti-influenza virus activity of the compounds was assessed in Madin-Darby canine kidney (MDCK) cells using the CCK-8 assay. The A / PR / 8 (PR) influenza strain was used to represent CPE caused by influenza virus infection. EC 50 The results were described as the concentration that provided 50% protection of cell viability after H1N1 virus infection. 50 μL of a dilution containing 100 TCID50 H1N1 influenza virus was mixed with an equal volume of serially 2-fold diluted compound solution. The mixture was added to MDCK cells pre-cultured in 96-well cells, 100 μL / well, with four replicates. The cells were incubated at 37°C in 5.0% CO2 atmosphere for 48 hours. Then, 10 μL of kit-8 (CCK-8) reagent solution and 100 μL of culture medium were added to each well. After incubation at 37°C for 90 minutes, the absorbance was read at 450 nm using a microplate reader. The EC50 of the oleanolic acid derivative was determined by fitting a curve of cell viability versus inhibitor concentration. 50 Value. OSC was used as a control drug. CC 50 The value was used to measure the cytotoxicity of the test compound to MDCK cells and compared with EC. 50 The same method was used for testing, but no viral infection was found. The results are shown in Table 1.

[0359] Table 1

[0360] 7 0.59μM 87.10μM 9 1.467μM 338.40μM 10 0.19μM 368.00μM 11 1.31μM 185.99μM 13 0.46μM 88.99μM 28 1.88μM 81.85μM Positive control drug 2.628μM >500μM

[0361] As can be seen from Table 1, the EC values ​​of the oleanolic acid derivatives provided by this invention are... 50 The values ​​were all very low, indicating a good inhibitory effect on the H1N1 influenza virus. However, direct testing with oleanolic acid revealed that CC... 50 The value was 44.36 μM, EC 50 Values ​​greater than 10 μM; the effect is very poor, and the anti-H1N1 influenza activity is almost undetectable.

[0362] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. An oleanolic acid derivative, characterized in that, It has the structure shown in Equation I: ； Among them, R1 is selected from H; R2 is selected from -CONHN=CHR and -CONHNHCH2R; R is selected from C 3~12 Aryl group; containing halogenated, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 At least one of the substituted C-halogenated alkyl groups and hydroxyl groups 3~12 The aryl group; the C 3~12 The aryl groups are phenyl, thiophene, pyridinyl, quinolinyl, isoquinolinyl, furanyl, imidazolyl, pyrroleyl, and thiazolyl.

2. An oleanolic acid derivative, characterized in that, The oleanolic acid derivative is selected from one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 3. The method for preparing the oleanolic acid derivative according to claim 1, characterized in that, Includes the following steps: The first reaction is carried out between compound III and compound 1; Alternatively, compound III, compound 2, and an organic base can undergo a second reaction; The structural formulas of compound III, compound 1, and compound 2 are as follows: 。 4. The preparation method according to claim 3, characterized in that, The first reaction satisfies at least one of the following conditions: i. The reaction temperature is 0℃~70℃; ii. The reaction time is 6.5h~11.5h.

5. The preparation method according to claim 3, characterized in that, The second reaction must satisfy at least one of the following conditions: i. The reaction temperature is 25℃~60℃; ii. The reaction time is 6.5h~11.5h; The molar ratio of compound 2, compound III, and organic base is 1:(2~4):(1~2).

6. A drug for treating H1N1 influenza A virus, characterized in that, Includes the oleanolic acid derivative as described in claim 1 or 2.

7. The use of the oleanolic acid derivative according to claim 1 or 2 in the preparation of drugs against H1N1 influenza A virus.

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