12-nitrogen substituted matrine ester derivative, preparation method and application thereof

Abstract

The invention discloses a 12-nitrogen substituted matrine ester derivative, a preparation method and an application thereof, and relates to the technical field of development and application of natural product derivatives of medicinal chemistry. Aiming at the disadvantages of the natural product matrine, such as low bioavailability, poor activity and large dosage, which limit its wide application, the invention hydrolyzes matrine and prepares matrine ester, and then replaces and transforms the 12-nitrogen substituted matrine ester derivatives to prepare a series of 12-nitrogen substituted matrine ester derivatives. Anti-tumor activity experiments show that the derivatives have good anti-cancer activity, and in particular have good inhibitory function on liver cancer and lung cancer cells.

Description

Technical Field

[0001] The present invention relates to the technical field of development and application of natural product derivatives of medicinal chemistry, and in particular to a 12-nitrogen substituted matrine derivative, a preparation method and application thereof. Background Art

[0002] Matrine is a tetracyclic quinolizine alkaloid isolated from the dried rhizomes of Sophora flavescens and Sophora flavescens. This ingredient has obvious pharmacological effects in antibacterial, anti-inflammatory, anti-allergic, anti-arrhythmic, immune and biological regulation. In recent years, it has received extensive attention due to its good anti-tumor activity. The spectrum of human diseases is also changing, and the types of tumors are gradually increasing. Matrine has the disadvantages of low bioavailability, poor activity, and large dosage, which limits its wide application. Summary of the invention

[0003] In view of the fact that there is no systematic study on the preparation of compounds of matrine ring-opening modification and anticancer activity at present, and there is no specific analysis on a certain type of structure and anticancer activity, the present invention optimizes the reaction route for the preparation of matrine derivatives and reduces the experimental cost. By optimizing the structure of open-ring matrine and introducing new groups, the inhibitory activity of the derivatives on liver cancer and lung cancer is increased.

[0004] To achieve the above object, the present invention provides the following solutions:

[0005] A 12-nitrogen substituted matrine ester derivative, wherein the 12-nitrogen of matrine is connected by a carbon chain and then substituted by a benzene ring, or the 12-nitrogen of matrine is substituted by an aromatic heterocycle, or the 12-nitrogen of matrine is substituted by a phenylthiadiazolecarbamoylmethyl group;

[0006] When the nitrogen at position 12 of matrine is connected by carbon chains of different lengths and then replaced by a benzene ring, the derivative is denoted as RO-A, and the structure is shown in general formula Ⅰ.

[0007]

[0008] In the general formula Ⅰ,

[0009] When the nitrogen at position 12 of matrine is replaced by different aromatic heterocycles, the derivative is recorded as RO-B. The aromatic heterocycles include quinoline ring, indole ring and naphthalene ring. The structure is shown in general formula II.

[0010]

[0011] In general formula II,

[0012] When the nitrogen at position 12 of matrine is replaced by a substituted phenylthiadiazole carboxamidomethyl group, the derivative is denoted as RO-C, and the structure is shown in general formula III.

[0013]

[0014] In general formula III,

[0015] A method for preparing the 12-nitrogen-substituted berberine acid ester derivatives, wherein the 12-nitrogen of berberine acid methyl ester is substituted with different groups to obtain different target derivatives. The reaction route of the derivatives having the general formula I structure is as follows:

[0016]

[0017] The reaction route of the derivatives having the general formula II is as follows:

[0018]

[0019] The reaction route of the derivatives having the general formula III is as follows:

[0020]

[0021] The specific steps include:

[0022] Methyl matrine and potassium carbonate were dissolved in 30-40 mL of anhydrous acetonitrile, nitrogen was introduced, and the mixture was stirred at room temperature for 30 min to obtain a first reaction solution. 2-chlorobenzyl bromide was then dissolved in acetonitrile and added dropwise to the first reaction solution. The mixture was stirred at room temperature for 8 h. After the reaction was completed as monitored by TLC, the solid was filtered and washed with ethyl acetate. The obtained liquid was extracted with deionized water, saturated brine was added, and the obtained organic layer was dried over anhydrous sodium sulfate. After 4 h, the organic layer was concentrated by rotary evaporation to obtain a pale yellow solid crude product. The crude product was separated by silica gel column chromatography to obtain a derivative RO-A1. Derivatives RO-A2 to RO-A14, RO-A17 to RO-A19, RO-B1, RO-B2 to RO-B4, and RO-B5 were synthesized by referring to the above method.

[0023] Methyl matrine was dissolved in 20 mL to 30 mL of anhydrous methanol, nitrogen was introduced, and the mixture was stirred at room temperature for 30 min. Lithium aluminum hydride was dissolved in 10 mL of anhydrous methanol under ice bath conditions to obtain a first reaction solution. Bromobenzene was then dissolved in 10 mL of anhydrous methanol. The methanol solution containing bromobenzene was added dropwise to the first reaction solution, and the mixture was stirred at room temperature for 8 h. After the reaction was completed by monitoring with TLC, a derivative RO-A15 was obtained. The derivative RO-A16 was prepared by the same method as above.

[0024] Dissolve triphenylphosphine and tetrabutylammonium bromide in 20 mL to 50 mL of dichloromethane, stir at room temperature for 0.5 h, then drop 0.68 mL of phenylpropanol, reflux at 120°C for 0.5 h to 1 h, until the reaction is completed as monitored by TLC, separate by silica gel column chromatography to obtain an intermediate product 1-bromo-3-phenylpropane; add 0.76 mL of phenylbutanol to a mixed system of triphenylphosphine and tetrabutylammonium bromide in the same manner as above to obtain an intermediate product 1-bromo-4-phenylbutane, react the above-obtained 1-bromo-3-phenylpropane and 1-bromo-4-phenylbutane with methyl berberine, respectively, and use the above-mentioned method for synthesizing RO-A1 to obtain derivatives RO-A20 and RO-A21;

[0025] Dissolve benzoic acid and semicarbazide in 1,4-dioxane solution, stir at room temperature, then add phosphorus oxychloride in an ice bath, stir thoroughly, heat and reflux at 75-80°C for 4-6 hours, cool to room temperature after the reaction, add ice water in batches until the phosphorus oxychloride in the solution is completely neutralized, filter the precipitated solid, wash twice with cold water, and dry the solid to obtain a crude intermediate product 2-amino-5-phenyl-1,3,4-thiadiazole, separate it by silica gel column chromatography to obtain a pure product, weigh 2g of 2-amino-5-phenyl-1,3,4-thiadiazole, react it with 0.9mL of chloroacetyl chloride to obtain 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole, and then refer to the synthesis method of derivative RO-A1 to react the intermediate product with methyl matrine to obtain derivatives RO-C1 to RO-C4;

[0026] 1.88 g of 3-indolecarboxaldehyde, 0.5 g of sodium borohydride and 2 g of methyl berberine were weighed into a 100 mL round-bottom flask, and 50 mL to 60 mL of anhydrous methanol were added under ice bath conditions. The reaction temperature was naturally restored to room temperature and the reaction was continued for 8 h until the reaction was completed as monitored by TLC to obtain derivatives RO-B6 and RO-B7.

[0027] The present invention allows matrine to be heated and refluxed under alkaline conditions for hydrolysis and ring opening to obtain open-ring matrine, and then undergoes a methylation reaction with methanol under thionyl chloride (dichlorothionyl) conditions to obtain matrine methyl ester, and introduces different substituents on the nitrogen at position 12 to obtain 12-nitrogen-substituted matrine ester derivatives RO-A1 to RO-A14; different aromatic bromides undergo substitution reactions on the nitrogen at position 12 under the alkaline conditions of potassium carbonate to obtain target compounds RO-A17 to RO-A21 with different carbon chain lengths; aromatic heteroformaldehyde undergoes a condensation reduction reaction with the nitrogen at position 12 under the action of sodium borohydride to obtain target compounds RO-B series; first, a benzoic acid compound undergoes a ring-forming reaction with semicarbazide, and then reacts with chloroacetyl chloride, and the obtained intermediate product undergoes a condensation reaction with matrine methyl ester to obtain target compounds RO-C series. A total of 32 target compounds were prepared for subsequent anti-tumor cell activity tests.

[0028] Preferably, the preparation method of methyl berberine is as follows: 10g to 15g of matrine is dissolved in a sodium hydroxide solution (mass fraction is 15% to 20%), refluxed at 120°C for 8 to 9h, after TLC monitoring the complete reaction, cooled to room temperature, white crystals are precipitated, filtered and dissolved with concentrated hydrochloric acid (concentration 37.5%), the obtained solution is concentrated to obtain a white solid, and dried at 50°C to obtain matrine, the matrine is dissolved in 30 to 50mL of anhydrous methanol, 12 to 15mL of dichlorothionyl is added dropwise under ice bath conditions, stirred at room temperature, refluxed at 70 to 80°C for 5 to 7h, after TLC monitoring the complete reaction, cooled to room temperature and concentrated, methanol solution is added for washing and concentration, washing and concentration are repeated 3 to 5 times, and then dried to obtain methyl berberine.

[0029] Preferably, in the method for preparing the 12-nitrogen-substituted matrine ester derivative, the material-liquid ratio of matrine to thionyl chloride is (10 g to 15 g): (12 mL to 15 mL).

[0030] Preferably, in the method for preparing the 12-position nitrogen-substituted berberine acid ester derivative, when synthesizing the derivative RO-A1, the mass ratio of berberine acid methyl ester to potassium carbonate is 1:3; the polarity of the eluent is: V 二氯甲烷 :V 甲醇 =50:1 to 40:1. The polarity of the eluent in the synthesis of other derivatives of the same derivative RO-A1 is the same as that in the synthesis of the derivative RO-A1.

[0031] Preferably, in the preparation method of the 12-nitrogen-substituted berberine acid ester derivative, when synthesizing the derivative RO-A15, the material-liquid ratio of berberine acid methyl ester, lithium aluminum hydride and bromobenzene is 2g:0.68g:0.64mL.

[0032] Preferably, in the method for preparing the 12-nitrogen-substituted berberine acid ester derivative, when synthesizing the derivative RO-A20, the mass ratio of triphenylphosphine to tetrabutylammonium bromide is 1.57:2.22; the polarity of the eluent is: V 石油醚 :V 乙酸乙酯 =3:1 to 1:1. The polarity of the eluent in the synthesis of other derivatives of the same derivative RO-A20 is the same as that in the synthesis of the derivative RO-A20.

[0033] Preferably, the synthesis method of the 12-nitrogen substituted berberine acid ester derivative RO-C1 of the present invention is as follows:

[0034]

[0035] Weigh 4.9g of benzoic acid and 3.65g of thiosemicarbazide in a 100mL round-bottom flask, add 10mL of 1,4-dioxane, stir at room temperature for 10min, add 14mL~20mL of phosphorus oxychloride under ice bath conditions, stir thoroughly for 0.5h, heat to reflux at 75~80℃, rise to 80℃, and react for 4h~6h. After the reaction is completed, cool to room temperature, add 15mL~16mL of ice water dropwise until the phosphorus oxychloride in the solution is completely neutralized, then filter the precipitated solid, wash twice with cold water, and dry the obtained solid to obtain the crude product of 2-amino-5-phenyl-1,3,4-thiadiazole, which is separated by silica gel column chromatography to obtain the pure product. Weigh 2g of 2-amino-5-phenyl-1,3,4-thiadiazole and react with 0.9mL of chloroacetyl chloride to obtain 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole. Then, the intermediate product 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole is subjected to a condensation reaction with matrine to obtain the derivative RO-C1.

[0036] The invention relates to an application of the 12-nitrogen substituted matrine derivative in the preparation of anti-tumor drugs.

[0037] The application of the 12-nitrogen substituted matrine derivative in the preparation of drugs for preventing and / or treating liver cancer and lung cancer.

[0038] The present invention discloses the following technical effects:

[0039] The invention aims at the disadvantages of the natural product matrine, such as low bioavailability, poor activity and large dosage, which limit its wide application. Matrine is hydrolyzed to prepare methyl matrine, and then a series of 12-nitrogen substituted matrine ester derivatives are prepared by substitution and modification at the 12-nitrogen position thereof. The anti-tumor activity experiment proves that the derivatives have good anti-cancer activity. The series of derivatives can be used for anti-tumor, and have good inhibitory function on liver cancer and lung cancer cells in particular. DETAILED DESCRIPTION

[0040] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0041] It should be understood that the terms described in the present invention are only for describing a particular embodiment and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. The intermediate value in any stated value or stated range, and each smaller range between any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0042] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0043] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to those skilled in the art. The present invention description and examples are exemplary only.

[0044] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0045] The room temperature in the present invention refers to 25±2°C.

[0046] Example 1

[0047] Preparation of derivative RO-A13:

[0048]

[0049] 10 g of matrine was added to a 250 mL round-bottom flask and dissolved in a 20% by mass sodium hydroxide solution. The mixture was refluxed at 120° C. for 8 hours. After TLC monitoring of the complete reaction, the mixture was cooled to room temperature to precipitate white crystals. The crystals were filtered and dissolved in concentrated hydrochloric acid (concentration of 37.5 wt%). The obtained solution was concentrated to finally obtain a white solid, which was dried in a vacuum drying oven at 50° C. to obtain 9.6 g of matrine with a yield of 95%.

[0050] The dried berberine acid was dissolved in 30 mL of anhydrous methanol, 12 mL of dichlorothione was added dropwise in an ice bath, and the mixture was stirred at room temperature for 10 min, refluxed at 70°C for 5 h, and the reaction was completed after TLC monitoring. The mixture was cooled to room temperature and concentrated, and methanol solution was added for washing and concentration. The washing and concentration were repeated 3 to 5 times, and then dried in a vacuum drying oven at 50°C to obtain 10.1 g of berberine acid methyl ester with a yield of 99.7%.

[0051] Weigh 2g of methyl berberine and 6g of potassium carbonate and dissolve them in 40mL of acetonitrile solution without water, introduce nitrogen, stir at room temperature for 30min to obtain the first reaction solution, then dissolve 2-fluoro-4-bromobenzyl bromide in acetonitrile solution, add dropwise to the first reaction solution, stir at room temperature for 8h, and terminate the reaction after monitoring the reaction by TLC. Filter the solid and rinse the solid with ethyl acetate. Extract the obtained liquid with deionized water, add saturated brine, dry the obtained organic layer with anhydrous sodium sulfate, and concentrate by rotary evaporation after 4h to obtain a pale yellow solid reaction crude product. Separate by silica gel column chromatography, the polarity of the eluent is V 二氯甲烷 :V 甲醇 =50:1, compound RO-A13 was obtained with a yield of 47%. RO-A1312 N-(2-fluoro-4-bromobenzyl)matrine methyl ester, oily substance, yield of 47%. 1 H NMR(600MHz, CDCl3)δ7.98(s,1H),7.58(s,1H),7.01(s,1H),3.65(s,3H),3 .48(s,1H),3.44(s,1H),3.20(s,1H),3.08(s,1H),2.95(s,1H),2.87(s,1H ),2.81(s,1H),2.43(s,2H),2.22(d,J=9.2Hz,1H),2.13(s,1H),1.93(s,3H ),1.78(d,J=12.3Hz,2H),1.69(s,1H),1.67(s,1H),1.58(d,J=14.2Hz,1H). 13C NMR(126MHz, CDCl3)δ174.06(s),163.36(s),131.12(s),127.81(s),125 .97(s),122.87(s),119.51(s),67.56(s),62.02(s),58.65(s),54.83(s) ,53.21(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s),29.06( s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 465.2553[M+H]+.

[0052] Derivatives RO-A1 to RO-A14, RO-A17 to RO-A19, RO-B1, RO-B2, RO-B4, RO-B5 were prepared by the same method as above, and the data obtained are as follows:

[0053] RO-A1 12N-(2-chlorobenzyl)matrine methyl ester, light yellow solid, yield 53%. mp 160.7-163.9℃. 1 H NMR (600MHz, CDCl3) δ7.28(s,1H),7.27(s,1H),7.20(s,1H),7.19(d,J=1.3Hz,1H),4.40(dd,J=12.7,4.3Hz,1H),3 .82(td,J=9.6,5.8Hz,1H),3.62(s,2H),3.57(t,J=7.7Hz,1H),3.16(t,J=7.6Hz,1H),3.05(t,J=12.7Hz,2H),2.84 (s,1H),2.82(d,J=2.1Hz,1H),2.80(s,2H),2.77(s,1H),2.41(t,J=3.7Hz,1H),2.29(d,J=4.0Hz,1H),2.26(dd,J= 11.0,5.6Hz,2H),2.23(d,J=5.3Hz,1H),2.08(s,1H),1.64(s,2H),1.44(s,1H),1.42(d,J=2.1Hz,1H),1.25(s,2H). 13C NMR(126MHz, CDCl3)δ169.43(s),128.88(s),128.72(s),128.65(s),128.61(s),12 8.46(s),128.42(s),63.80(s),57.31(s),57.24(s),53.21(s),52.41(s),52.40(s) ),51.44(s),43.24(s),41.46(s),39.43(s),35.34(s),32.87(s),27.77(s),27.17 (s),26.48(s),21.20(s),20.79(s),19.01(s).LC-MS(ESI):m / z383.3623[M+Na]+.

[0054] RO-A2 12N-(2-bromobenzyl)matrine methyl ester, yellow solid, yield 71%, mp 165.3-167.4℃. 1 HNMR(600MHz, CDCl3)δ7.59(d,J=7.6Hz,1H),7.50(d,J=1.1Hz,1H),7.48(d,J=1.1Hz,1H), 7.06(td,J=7.8,1.6Hz,1H),3.98(d,J=15.2Hz,1H),3.40(d,J=15.2Hz,1H),3.01(d,J=4.1 Hz,1H),2.83(d,J=9.7Hz,2H),2.78(d,J=11.7Hz,1H),2.34(d,J=3.5Hz,1H),2.31(s,1H), 2.23(s,1H),2.22(s,1H),2.06(s,1H),1.91(s,1H),1.88(s,2H),1.67(s,1H),1.66(s,1H). 13 C NMR(126MHz, CDCl3)δ174.10(s),139.60(s),132.79(s),132.39(s),130.10 (s),127.77(s),127.33(s),124.03(s),65.63(s),64.61(s),57.59(s),57. 36(s),57.21(s),55.11(s),52.49(s),51.39(s),38.07(s),34.18(s),33.7 5(s),28.69(s),28.15(s),27.26(s),21.60(s),21.35(s).LC-MS(ESI):m / z 449.1699[M+H]+.

[0055] RO-A3 12N-(2-fluorobenzyl)matrine methyl ester, yellow solid, yield 65%, mp 155.3-157.7°C. 1 HNMR (600MHz, CDCl3) δ7.46 (s, 1H), 7.20 (d, J = 6.6Hz, 1H), 7.09 (t, J = 7.3Hz, 2H), 7.00 (d, J = 9. 2Hz,1H),4.04(d,J=16.3Hz,1H),3.63(s,6H),3.28(d,J=8.0Hz,1H),2.92(s,1H),2.84(s,2H) ,2.76(s,3H),2.37(s,1H),2.29(d,J=6.2Hz,3H),2.05(s,1H),1.90(d,J=13.6Hz,4H),1.77(s ,6H),1.75(s,2H),1.72(d,J=5.3Hz,3H),1.44(s,1H),1.40(s,3H),1.37(s,1H),1.25(s,1H). 13 C NMR(126MHz, CDCl3)δ174.13(s),162.35(s),160.40(s),123.94(s),115.19(s),115.01(s),64.50(s),57.49(s),57.27(s),52.02(s),51.4 5(s),49.00(s),37.94(s),37.92(s),34.19(s),33.66(s),28.63(s),28.03(s),27.15(s),21.48(s),21.22(s),19.39(s).LC-MS(ESI):m / z 389.2512[M+H]+.

[0056] RO-A4 12N-(3-chlorobenzyl)matrine methyl ester, light yellow solid, yield 54%, mp 97.1-97.5℃. 1HNMR (600MHz, CDCl3) δ7.39 (s, 1H), 7.35 (s, 1H), 7.30 (d, J = 1.3Hz, 1H), 7.29 (s, 1H), 4.54 (s, 2H), 3.63(s,6H),3.09(s,2H),2.84(s,2H),2.76(d,J=9.1Hz,1H),2.62(s,2H),2.27(d,J=4.2Hz,5H), 2.11(s,1H),2.04(s,2H),1.89(d,J=13.5Hz,4H),1.68(d,J=7.0Hz,6H),1.65(s,11H),1.57(d,J= 13.4Hz,3H),1.41(s,2H),1.25(s,2H),1.21(t,J=7.1Hz,1H),1.10(s,1H),0.88(t,J=6.9Hz,1H). 13 C NMR(126MHz, CDCl3)δ174.04(s),139.30(s),134.51(s),130.00(s),128.70(s),128.56(s),126.64(s),57.29(s),56.19(s),51.49(s) ,45.24(s),38.15(s),34.11(s),34.03(s),32.11(s),31.24(s),29.70(s),28.46(s),27.17(s),21.32(s),19.12(s).LC-MS(ESI):m / z 430.9036[M+Na]+.

[0057] RO-A5 12N-(3-bromobenzyl)matrine methyl ester, yellow solid, yield 63%, mp 96.5-96.9℃. 1 HNMR(600MHz, CDCl3)δ7.49(s,1H),7.34(d,J=7.8Hz,1H),7.25(s,1H),7.16(t,J=7.7Hz,1H), 4.04(d,J=13.7Hz,1H),3.63(s,4H),3.07(d,J=13.6Hz,1H),2.84(t,J=11.7Hz,2H),2.76(d,J =11.0Hz,1H),2.62(t,J=11.7Hz,1H),2.30(s,1H),2.28(s,1H),2.27(d,J=2.9Hz,1H),2.26(s ,1H),2.04(s,1H),1.89(d,J=14.0Hz,3H),1.70(s,2H),1.68(s,2H),1.55(s,1H),1.25(s,1H).13 C NMR(126MHz, CDCl3)δ174.07(s),143.27(s),131.38(s),129.77(s),129 .65(s),127.15(s),122.44(s),65.13(s),64.49(s),57.60(s),57.36(s) ,56.22(s),52.43(s),51.47(s),38.11(s),34.21(s),34.05(s),28.57( s),28.15(s),27.29(s),21.62(s),21.39(s),19.21(s).LC-MS(ESI):m / z 430[M+Na]+.

[0058] RO-A6 12N-(3-fluorobenzyl)matrine methyl ester, white solid, yield 64%, mp 94.9-95.2℃. 1 HNMR (600MHz, CDCl3) δ7.23 (dd, J=7.8, 1.9Hz, 1H), 7.09 (s, 1H), 7.08 (s, 1H), 6.89 (td, J=8. 3,2.1Hz,1H),4.07(d,J=13.8Hz,1H),3.61(s,4H),3.12(d,J=13.2Hz,1H),3.04(s,1H),2.9 0(s,1H),2.66(s,1H),2.27(s,1H),2.26(s,1H),2.25(d,J=4.2Hz,1H),1.90(d,J=11.8Hz,2 H),1.73(s,1H),1.69(s,1H),1.44(d,J=3.1Hz,1H),1.41(s,1H),1.38(s,1H),1.36(s,1H). 13 C NMR (126MHz, CDCl3) δ174.05 (s), 164.00 (s), 162.06 (s), 129.54 (d, J = 8.2Hz) ,124.07(s),115.17(d,J=21.3Hz),113.42(d,J=21.4Hz),64.55(s),63.79(s) ,57.48(s),57.29(s),57.26(s),57.22(s),56.13(s),51.44(s),37.97(s),34 .16(s),33.95(s),28.44(s),27.16(s),21.17(s),19.06(s).LC-MS(ESI):m / z 389.2501[M+H]+.

[0059] RO-A7 12N-(4-chlorobenzyl)matrine methyl ester, white solid, yield 72%, mp 109.2-109.8℃. 1 HNMR (600MHz, CDCl3) δ7.30 (s, 1H), 7.28 (s, 6H), 7.27 (s, 1H), 7.26 (s, 1H), 4.06 (d, J = 13.5Hz, 5H), 3.64 (s, 1 8H),3.08(d,J=13.4Hz,6H),2.85(d,J=11.9Hz,13H),2.78(d,J=10.4Hz,6H),2.62(t,J=11.6Hz,6H),2.29(t ,J=6.5Hz,18H),2.05(s,5H),1.97(d,J=6.3Hz,2H),1.91(d,J=8.6Hz,7H),1.89(s,6H),1.87(s,4H),1.80–1 .77(m,7H),1.71(s,11H),1.45(d,J=4.1Hz,5H),1.42(s,5H),1.38(d,J=3.0Hz,10H),1.23(t,J=7.1Hz,1H). 13 C NMR(126MHz, CDCl3)δ174.07(s),139.09(s),132.10(s),129.92(s),128.30(s),64.50(s),57.59(s),57.35(s),55.97(s),52.23(s),51.45(s) ,38.07(s),34.21(s),34.06(s),28.51(s),28.16(s),27.29(s),27.16 (s),21.62(s),21.38(s),19.14(s).LC-MS(ESI):m / z383.3614[M+Na]+.

[0060] RO-A8 12N-(4-bromobenzyl)matrine methyl ester, yellow block solid, yield 78%, mp 109.0-110.1℃. 1H NMR (600MHz, CDCl3) δ7.29(d,J=2.6Hz,1H),7.27(s,1H),6.98(d,J=2.1Hz,1H),6.96(s,1H),4.00 (dd,J=26.4,13.3Hz,1H),3.61(s,2H),3.04(t,J=14.2Hz,1H),2.83(d,J=2.5Hz,1H),2.75(d,J=10 .5Hz,1H),2.58(td,J=12.0,3.3Hz,1H),2.28(s,1H),2.27(s,1H),2.02(s,1H),1.89(s,1H),1.86( s,1H),1.69(s,1H),1.68(s,1H),1.42(s,1H),1.39(s,1H),1.36(s,1H),1.35(s,1H),1.33(s,1H). 13 C NMR(126MHz, CDCl3)δ174.07(s),139.07(s),132.11(s),129.93(s),129.6 8(s),128.30(s),128.01(s),64.49(s),63.79(s),57.58(s),57.34(s),57. 23(s),55.98(s),52.23(s),51.45(s),38.07(s),34.20(s),34.05(s),28.5 1(s),28.16(s),27.28(s),21.61(s),21.37(s),19.14(s).LC-MS(ESI):m / z 449.1687[M+H]+.

[0061] RO-A9 12N-(3-methylbenzyl)matrine methyl ester, white powder, yield 74%, mp 84.9-85.1℃. 1HNMR (600MHz, CDCl3) δ7.24(t,J=7.9Hz,1H),7.02(s,1H),6.96(d,J=7.5Hz,1H),6.82(dd,J=8.1,2.3Hz,1H),4 .24(d,J=13.4Hz,1H),3.82(s,3H),3.65(s,3H),3.34(d,J=13.4Hz,1H),3.05(t,J=9.5Hz,2H),2.97(s,1H),2. 79(dd,J=15.8,8.6Hz,1H),2.52(dd,J=11.8,4.0Hz,1H),2.33(td,J=6.6,2.1Hz,2H),2.27(s,1H),2.05(d,J=2 .4Hz,1H),2.03(s,4H),1.97(s,1H),1.94(s,1H),1.81(s,1H),1.73(d,J=2.6Hz,1H),1.49(s,1H),1.41(s,1H). 13 CNMR(126MHz,CDCl3)δ175.84(s),174.00(s),159.72(s),129.31(s),12 1.63(s),114.74(s),112.79(s),64.11(s),57.92(s),57.05(s),56.87(s) ),56.48(s),55.21(s),51.51(s),37.73(s),33.94(s),33.19(s),28.45( s),27.51(s),26.72(s),20.87(s),20.74(s),19.69(s).LC-MS(ESI):m / z 383.1735[M+Na]+.

[0062] RO-A10 12N-(4-methylbenzyl)matrine methyl ester, oily droplets, yield 52%. 1H NMR (600MHz, CDCl3) δ7.41(s,1H),7.30(s,1H),7.27(s,1H),7.27(s,1H),4.39(dd,J=12.8,4.1Hz,1 H),4.11(s,1H),3.83(s,1H),3.62(s,2H),3.10(s,1H),2.83(d,J=36.5Hz,2H),2.39(d,J=3.7Hz,1H ),2.28(d,J=6.4Hz,1H),2.24(d,J=5.5Hz,1H),2.23(s,1H),2.22(d,J=5.4Hz,1H),1.96(s,2H),1.9 0(s,1H),1.88(s,1H),1.78(s,1H),1.68(s,1H),1.66(s,1H),1.44(s,1H),1.42(s,1H),1.24(s,1H). 13 C NMR(126MHz, CDCl3)δ174.00(s),169.53(s),164.52(s),163.12(s),130.21(s),128.49(s),63.82(s),57.24(s),57.17(s),56.97(s),53.4 4(s),53.15(s),51.53(s),43.17(s),41.42(s),35.28(s),33.91(s),32.81(s),29.70(s),28.18(s),27.16(s),18.93(s).LC-MS(ESI):m / z 385.3405[M+H]+.

[0063] RO-A11 12N-(2-bromo-4-fluorobenzyl)matrine methyl ester, oily droplets, yield 48%. 1 H NMR(600MHz, CDCl3)δ7.98(s,1H),7.58(s,1H),7.01(s,1H),3.65(s,3H),3 .48(s,1H),3.44(s,1H),3.20(s,1H),3.08(s,1H),2.95(s,1H),2.87(s,1H ),2.81(s,1H),2.43(s,2H),2.22(d,J=9.2Hz,1H),2.13(s,1H),1.93(s,3H ),1.78(d,J=12.3Hz,2H),1.69(s,1H),1.67(s,1H),1.58(d,J=14.2Hz,1H). 13C NMR(126MHz, CDCl3)δ173.69(s),162.14(s),160.46(s),147.63(s),128 .15(s),125.08(s),119.25(s),55.99(s),51.69(s),49.70(s),49.62(s) ,49.57(s),49.50(s),44.42(s),36.45(s),32.88(s),29.64(s),28.21( s),25.79(s),25.46(s),25.00(s),24.84(s),18.74(s).LC-MS(ESI):m / z 467.1596[M+H]+.

[0064] RO-A12 12N-(3,4-difluorobenzyl)matrine methyl ester, oily droplets, yield 42%. 1 H NMR(600MHz, CDCl3)δ7.98(s,1H),7.58(s,1H),7.01(s,1H),4.59(s,2H),4.33(s, 1H),3.65(s,3H),3.48(s,1H),3.47(d,J=38.8Hz,3H),3.20(s,1H),3.08(s,1H),2. 95(s,1H),2.84(d,J=37.2Hz,3H),2.43(s,2H),2.23(s,1H),2.13(s,1H),1.93(s, 3H),1.79(s,1H),1.77(s,1H),1.69(s,1H),1.67(s,1H),1.60(s,1H),1.57(s,1H). 13 C NMR(126MHz, CDCl3)δ174.06(s),163.42(s),161.40(s),132.03(s),130 .80(s),129.04(s),122.05(s),115.19(s),67.56(s),62.02(s),60.46(s) ),54.83(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s),29.06( s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 430.9032[M+Na]+.

[0065] RO-A14 12N-(4-methoxybenzyl)matrine methyl ester, oil droplets, yield 65%. 1H NMR (600MHz, CDCl3) δ7.24(t,J=7.9Hz,1H),7.02(s,1H),6.96(d,J=7.5Hz,1H),6.82(dd,J=8.1,2.3Hz,1H),4. 24(d,J=13.4Hz,1H),3.82(s,3H),3.65(s,3H),3.34(d,J=13.4Hz,1H),3.05(t,J=9.5Hz,2H),2.97(s,1H),2.7 9(dd,J=15.8,8.6Hz,1H),2.52(dd,J=11.8,4.0Hz,1H),2.33(td,J=6.6,2.1Hz,2H),2.27(s,1H),2.05(d,J=2. 4Hz,1H),2.03(s,4H),1.97(s,1H),1.94(s,1H),1.81(s,1H),1.73(d,J=2.6Hz,1H),1.49(s,1H),1.41(s,1H). 13 CNMR(126MHz,CDCl3)δ175.84(s),174.00(s),159.72(s),129.31(s),12 1.63(s),114.74(s),112.79(s),64.11(s),57.92(s),57.05(s),56.87(s) ),56.48(s),55.21(s),51.51(s),37.73(s),33.94(s),33.19(s),28.45( s),27.51(s),26.72(s),20.87(s),20.74(s),19.69(s).LC-MS(ESI):m / z 401.2706[M+H]+.

[0066] RO-A17 12N-phenylethyl berberine acid methyl ester, oil, yield 45%. 1H NMR (600MHz, CDCl3) δ7.59(d,J=7.5Hz,1H),7.32(s,1H),7.30(s,1H),7.23(t,J=7.4Hz,1H),7.13(s, 1H),4.01(d,J=15.0Hz,1H),3.61(s,2H),3.41(d,J=15.0Hz,1H),2.99(d,J=10.6Hz,1H),2.85(d,J=11 .3Hz,1H),2.79(s,1H),2.77(s,1H),2.32(dt,J=11.4,5.7Hz,1H),2.25(s,1H),2.23(d,J=5.5Hz,1H) ,2.06(s,1H),1.88(s,1H),1.72(d,J=3.4Hz,1H),1.69(s,1H),1.61(s,3H),1.40(s,1H),1.36(s,2H). 13 C NMR(126MHz, CDCl3)δ174.13(s),138.04(s),133.77(s),130.05(s),129 .13(s),127.42(s),126.69(s),64.60(s),57.63(s),57.40(s),57.35(s) ,52.58(s),52.50(s),51.40(s),38.11(s),34.23(s),33.81(s),28.74( s),28.20(s),27.29(s),21.64(s),21.40(s),19.61(s).LC-MS(ESI):m / z 430.9122[M+Na]+.

[0067] RO-A18 12N-(2-fluoro-phenethyl)matrine methyl ester, brown solid, yield 48%, mp 67.4-68.5℃. 1 H NMR (600MHz, CDCl3) δ7.37(s,1H),7.31(s,1H),7.28(s,1H),7.10(s,1H),3.85(t,J= 14.9Hz,1H),3.61(s,4H),3.05(s,1H),2.76(t,J=14.9Hz,3H),2.46(d,J=30.9Hz,3H ),2.46(d,J=9.4Hz,1H),2.35(s,1H),2.04(s,1H),2.01(s,1H),1.79(s,1H),1.77(s ,1H),1.74(s,1H),1.70(s,1H),1.53(s,1H),1.45(s,1H),1.45(s,1H),1.43(s,1H).13 C NMR(126MHz, CDCl3)δ169.50(s),136.58(s),126.67–126.36(m),123.09(s),122.22( s),119.69(s),119.00(s),116.20(s),111.32(s),63.77(s),58.29(s),58.55–58.01 (m),57.29(s),57.21(s),53.20(s),43.22(s),41.46(s),35.33(s),32.83(s),27.75 (s),27.14(s),26.45(s),21.17(s),20.76(s),18.96(s),18.43(s).LC-MS(ESI):m / z 405.2317[M+H]+.

[0068] RO-A19 12N-(4-methylphenethyl)matrine methyl ester, white solid, yield 23%, mp 84.9-85.1℃. 1 H NMR (600MHz, DMSO) δ7.07(s,1H),7.05(d,J=2.6Hz,3H),7.00(d,J=2.6Hz,3H),6.98(s,1H),3. 82(s,3H),3.62(s,8H),3.04(d,J=5.6Hz,1H),2.74(s,5H),2.46(d,J=30.9Hz,6H),2.35(s,2H) ,2.19(s,8H),2.04(s,1H),2.00(s,1H),1.78(d,J=1.1Hz,1H),1.76(s,1H),1.75(s,1H),1.53( s,1H),1.51(s,1H),1.47(s,1H),1.45(s,2H),1.43(s,2H),1.42(d,J=2.9Hz,1H),1.38(s,1H). 13 C NMR(126MHz, DMSO)δ174.06(s),151.01(s),146.80(s),134.15(s),126.44(s),116.21(s),115.85(s),67.56(s),62.02(s),60.97(s),54.8 3(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s),29.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 413.2673[M+NH4]+.

[0069] RO-B1 12N-(2-quinolinylmethyl)matrine methyl ester, brown solid, yield 56%, mp 63.2-64.7℃. 1 HNMR (600MHz, CDCl3) δ8.12(d,J=8.5Hz,1H),8.05(d,J=8.5Hz,1H),7.79(d,J=8.1Hz,1H),7.75(d,J=8.5Hz, 1H),7.68(ddd,J=8.4,6.9,1.4Hz,1H),4.30(d,J=14.8Hz,1H),3.59(s,3H),3.10(s,1H),3.08(s,1H),2.93(t ,J=12.0Hz,1H),2.85(d,J=10.4Hz,1H),2.77(d,J=10.8Hz,1H),2.35(dd,J=11.8,3.9Hz,1H),2.23(t,J=7.1 Hz,2H),2.09(s,1H),1.95(d,J=1.4Hz,1H),1.93(s,1H),1.91(s,1H),1.89(s,1H),1.74(s,1H),1.73(s,1H). 13 C NMR(151MHz, CDCl3)δ174.06(s),158.26(s),144.76(s),134.77(s),130.51(s),1 27.79(s),127.25(s),126.57(s),125.75(s),121.75(s),67.56(s),63.14(s),62 .02(s),54.83(s),53.21(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s) ,29.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 445.1113[M+Na]+.

[0070] RO-B2 12N-(5-quinolinylmethyl)matrine methyl ester, dark yellow solid, yield 72%, mp 26.3-26.4℃. 1HNMR (600MHz, CDCl3) δ8.80(d,J=4.4Hz,1H),8.07(d,J=8.4Hz,1H),7.92(d,J=8.3Hz,1H),7.66(t,J=7.1Hz,1H),7.55(d, J=4.4Hz,1H),7.51(t,J=7.2Hz,1H),4.32(dd,J=12.8,4.3Hz,2H),3.77(td,J=9.6,6.0Hz,2H),3.00(s,1H),2.76(dd,J=33 .8,11.4Hz,3H),2.37(t,J=3.6Hz,1H),2.34(t,J=3.7Hz,1H),2.18(s,1H),2.04(s,1H),1.95(d,J=2.2Hz,1H),1.93(d,J= 1.9Hz,1H),1.90(d,J=1.6Hz,1H),1.88(d,J=2.7Hz,1H),1.85(s,1H),1.83(s,1H),1.68(s,1H),1.61(s,1H),1.59(s,1H). 13 C NMR(126MHz, CDCl3)δ174.06(s),149.57(s),147.73(s),137.60(s),130.46(s) ),129.75(s),128.44(s),126.38(s),120.83(s),120.44(s),67.56(s),62.02( s),60.77(s),54.83(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s),2 9.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 430.9049[M+H]+.

[0071] RO-B3 12N-(3-quinolinylmethyl)matrine methyl ester, oil, 83%. 1H NMR (600MHz, CDCl3) δ8.82(d,J=4.4Hz,1H),8.10(d,J=8.4Hz,1H),7.94(d,J=8.3Hz,1H),7.68(t,J=7.1Hz,1H),7.57(d ,J=4.4Hz,1H),7.53(t,J=7.2Hz,1H),4.35(dd,J=12.8,4.3Hz,2H),3.79(td,J=9.6,6.0Hz,2H),3.02(s,1H),2.79(dd, J=33.8,11.4Hz,3H),2.40(t,J=3.8Hz,1H),2.37(t,J=3.7Hz,1H),2.20(s,1H),2.06(s,2H),1.95(d,J=1.9Hz,1H),1.9 2(d,J=1.6Hz,1H),1.88(s,1H),1.85(s,1H),1.70(s,1H),1.64(s,1H),1.61(d,J=1.0Hz,1H),1.59(s,1H),1.48(s,1H). 13 C NMR(126MHz, CDCl3)δ169.60(s),150.31(s),147.63(s),147.21(s),129.81(s),129.1 6(s),126.54(s),125.89(s),122.92(s),118.13(s),63.69(s),61.10(s),57.24(s),5 7.16(s),53.18(s),43.16(s),41.47(s),35.29(s),32.74(s),27.69(s),27.06(s),26 .39(s),21.12(s),20.70(s),18.86(s),18.41(s).LC-MS(ESI):m / z362.9172[M+Na]+.

[0072] RO-B4 12N-(β-naphthylmethyl)matrine methyl ester, oil, yield 52%. 1H NMR (600MHz, CDCl3) δ8.01(t,J=3.0Hz,1H),7.96(d,J=2.9Hz,1H),7.72(t,J=2.9Hz,1H),7.69–7.69(m,1H), 7.57(d,J=1.6Hz,1H),7.34(s,1H),7.28(d,J=1.0Hz,1H),7.00(d,J=5.7Hz,1H),5.22(s,2H),3.62(s,7H),3 .38(s,2H),2.84(s,1H),2.49(s,2H),2.43(s,1H),2.35(s,1H),2.09(s,1H),2.04(s,2H),2.00(s,1H),1.82 (s,1H),1.79(s,2H),1.68(s,1H),1.64(s,1H),1.63(s,1H),1.47(d,J=1.7Hz,1H),1.45(s,2H),1.43(s,1H). 13 C NMR(151MHz, CDCl3)δ174.06(s),133.27(s),131.94(s),129.56(s),128.73(s),1 27.79(s),127.35(s),126.91(s),126.84(s),126.14(s),124.79(s),67.56(s),6 2.02(s),60.77(s),54.83(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s) ),29.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 430.9051[M+H]+.

[0073] RO-B5 12N-(α-naphthylmethyl)matrine methyl ester, oil, yield 47%. 1H NMR (600MHz, CDCl3) δ8.12(s,1H),7.84(s,2H),7.83(s,1H),7.81(d,J=8.6Hz,2H),7.76(s,2H),7.54(d,J=8.1Hz ,2H),7.46(td,J=7.2,1.3Hz,4H),4.29(dd,J=11.0,5.2Hz,4H),3.64(s,8H),3.28(d,J=13.2Hz,3H),2.94(d,J=9. 4Hz,2H),2.88(d,J=11.0Hz,3H),2.80(d,J=10.9Hz,3H),2.67(t,J=11.7Hz,2H),2.34(d,J=1.9Hz,1H),2.33(d,J= 1.3Hz,1H),2.32(s,1H),2.08(s,3H),1.97(s,2H),1.45(s,1H),1.40(s,1H),1.28(s,19H),0.98(t,J=7.5Hz,3H). 13 C NMR(126MHz, CDCl3)δ174.06(s),135.98(s),133.66(s),133.02(s),128.90(s),1 28.82(s),127.77(s),126.92(s),126.71(s),126.17(s),125.98(s),67.56(s),6 2.02(s),61.06(s),54.83(s),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s) ),29.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 422.2717[M+H]+.

[0074] Example 2

[0075] Preparation of derivative RO-A15

[0076]

[0077] Weigh 2 g of methyl berberine and dissolve it in 30 mL of anhydrous methanol. Pass nitrogen and stir at room temperature for 30 min. Dissolve 0.68 g of lithium aluminum hydride in 10 mL of anhydrous methanol under ice bath conditions. Then dissolve (substituted) bromobenzene in 10 mL of anhydrous methanol solution, add dropwise to the reaction solution, stir at room temperature for 8 h, and monitor the reaction by TLC.

[0078] RO-A15 and RO-A16 were prepared by the above method, and the obtained data are as follows:

[0079] RO-A15 12N-phenylmatrine methyl ester, white flaky solid, yield 43%, mp 65.2-66.3. 1 H NMR (600MHz, CDCl3) δ7.25 (s, 1H), 7.24 (d, J = 0.7Hz, 2H), 7.22 (s, 1H), 7.16 (s, 3H), 7.14 (s, 3H), 4.36 (d, J = 4.4Hz, 6H), 4.3 3(d,J=4.4Hz,6H),3.77(dd,J=9.9,3.8Hz,10H),3.57(s,8H),3.00(t,J=12.7Hz,17H),2.80(s,1H),2.78(d,J=2.7Hz,4H),2 .75(s,2H),2.72(s,3H),2.39(td,J=4.6,1.4Hz,6H),2.36(td,J=4.5,1.4Hz,8H),2.25(d,J=2.8Hz,3H),2.21(d,J=5.4Hz,4 H),2.20(s,3H),2.17(d,J=5.5Hz,3H),2.04(s,6H),1.90(s,3H),1.64(d,J=2.9Hz,9H),1.39(d,J=1.2Hz,9H),1.37(s,8H). 13 C NMR(126MHz, CDCl3)δ173.89(s),169.45(s),128.67(s),128.38(s),125.93(s),63.72(s),57.25(s),57.18(s),53.16(s),51.40(s), 43.19(s),41.43(s),35.30(s),34.27(s),32.78(s),27.72(s),27.11(s),26.42(s),21.14(s),20.73(s),18.93(s).LC-MS(ESI):m / z 371.2704[M+NH4]+.

[0080] RO-A16 12N-(4-nitrophenyl)matrine methyl ester, brown block solid, yield 56%, mp 74.9-75.0℃. 1H NMR (600MHz, CDCl3) δ8.09(d,J=9.0Hz,1H),7.68(d,J=9.1Hz,1H),7.29(d,J=7.4Hz,3H),7.21(d,J=7.6Hz,4H),4.38(dd,J=1 2.8,4.3Hz,6H),3.60(s,4H),3.46(s,13H),3.04(t,J=12.7Hz,9H),2.81(dd,J=25.1,9.1Hz,15H),2.43(t,J=3.7Hz,3H),2.3 9(t,J=4.0Hz,4H),2.33(t,J=6.3Hz,3H),2.26(s,1H),2.25(d,J=5.5Hz,2H),2.23(s,2H),2.20(d,J=5.5Hz,2H),1.96(d,J=1 2.3Hz,12H),1.88(d,J=13.8Hz,11H),1.68(s,10H),1.65(d,J=1.7Hz,6H),1.43(d,J=5.2Hz,8H),1.41(s,11H),1.24(s,6H). 13 C NMR(126MHz, CDCl3)δ169.53(s),132.62(s),128.72(s),125.00(s),63.79(s),57.25(s),57.18(s),50.74(s),43.19 (s),41.44(s),35.30(s),32.80(s),27.69(s),27.15(s),26.39(s),21.11(s),20.70(s),18.93(s).LC-MS(ESI):m / z 402.1584[M+H]+.

[0081] Example 3

[0082] Preparation of compound RO-A20:

[0083]

[0084] 1.57 g of triphenylphosphine and 2.22 g of tetrabutylammonium bromide were dissolved in 30 mL of dichloromethane, stirred at room temperature for 0.5 h, and then 0.68 mL of phenylpropanol was added dropwise, and refluxed at 120° C. for 0.5 h until the reaction was completed as monitored by TLC. Then, silica gel column chromatography was used for separation, and the polarity of the eluent was: petroleum ether: ethyl acetate = 3:1 (V:V), to obtain the desired intermediate product 1-bromo-3-phenylpropane.

[0085]

[0086] In the same manner as above, 0.76 mL of phenylbutanol was added to a mixture of triphenylphosphine and tetrabutylammonium bromide to obtain the intermediate product 1-bromo-4-phenylbutane.

[0087] The obtained 1-bromo-3-phenylpropane and 1-bromo-4-phenylbutane were reacted with methyl berberine respectively, referring to the methods A-1 to A-14 above, to obtain the target compounds RO-A20 and RO-A21.

[0088] RO-A20 12N-(3-phenylpropyl)matrine methyl ester, oil, yield 44%. 1 H NMR (600MHz, DMSO) δ8.30(d,J=8.5Hz,1H),7.94(dd,J=16.4,8.3Hz,2H),7.71(qd,J=6.7,3.2Hz,1H),7.64(d,J=8.5Hz,1H),7. 55(t,J=6.9Hz,1H),4.24(d,J=14.4Hz,1H),3.50(s,3H),3.45(d,J=14.3Hz,1H),3.34(s,5H),2.94(d,J=10.4Hz,1H),2.90(s,1 H),2.78(d,J=5.8Hz,1H),2.77(s,1H),2.75(s,1H),2.50(dt,J=3.6,1.8Hz,1H),2.23(t,J=7.1Hz,2H),2.20(d,J=8.7Hz,1H), 2.12(dd,J=10.6,5.5Hz,1H),1.99(s,1H),1.86(s,1H),1.84(s,1H),1.70(d,J=4.1Hz,1H),1.25(s,1H),1.23(d,J=8.9Hz,1H). 13 C NMR(126MHz,DMSO)δ173.89(s),147.43(s),136.73(s),129.79(s),128.86(s), 128.22(s),127.41(s),126.38(s),120.94(s),64.22(s),63.62(s),58.53(s),5 7.14(s),57.06(s),57.00(s),53.08(s),51.55(s),37.71(s),35.83–35.52(m), 33.69(s),32.94(s),27.91(s),21.20(s),19.09(s),18.98(s).LC-MS(ESI):m / z 422.2697[M+Na]+.

[0089] RO-A21 12N-(4-phenylbutyl)matrine methyl ester, oil, yield 41%. 1 H NMR(600MHz,DMSO)δ7.24(s,1H),7.23(s,1H),7.22(s,9H),7.21(s,1H),7.20(s,1H),3.61(s,13 H),2.98(d,J=14.1Hz,2H),2.93(d,J=14.2Hz,2H),2.63(s,9H),2.50(s,2H),2.49(s,3H),2.42(s ,7H),2.39(d,J=4.6Hz,3H),2.34(s,4H),2.03(s,2H),1.94(s,1H),1.91(s,1H),1.77(s,1H),1.7 6(s,1H),1.73(d,J=4.3Hz,3H),1.53(s,4H),1.51(s,2H),1.48(s,1H),1.47(s,2H),1.42(s,2H). 13 C NMR(125MHz,DMSO)δ174.06(s),142.31(s),129.22(s),129.22(s),128.33(s) ),128.33(s),126.17(s),67.56(s),63.73(s),55.26(s),54.53(s),53.21(s) ,51.87(s),40.87(s),37.94(s),36.31(s),33.71(s),29.06(s),28.28(s),27 .99(s),26.71(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 413.2678[M+H]+.

[0090] Example 4

[0091] Preparation of compound RO-B6:

[0092]

[0093] 1.88 g of 3-indolecarboxaldehyde, 0.5 g of sodium borohydride and 2 g of methyl berberine were weighed into a 100 mL round-bottom flask, and 50 mL of anhydrous methanol was added under ice bath conditions. The reaction temperature naturally rose to room temperature and the reaction was continued for 8 h until the reaction was completed as monitored by TLC to obtain compound RO-B6.

[0094] RO-B6 12N-(3-indolemethyl)matrine methyl ester, brown solid, yield 53%, mp 50.0-50.2℃. 1HNMR (600MHz, CDCl3) δ8.55(s,1H),7.73(d,J=7.9Hz,1H),7.37(d,J=8.1Hz,1H),7.20(s,1H),7.14(s,1H) ,4.88(s,1H),4.38(dd,J=12.8,4.4Hz,4H),3.80(td,J=9.7,5.8Hz,4H),3.04(t,J=12.7Hz,4H),2.83(d,J =10.3Hz,4H),2.77(d,J=11.5Hz,4H),2.43(td,J=4.5,1.4Hz,2H),2.40(td,J=4.5,1.4Hz,2H),2.26(s,1H ),2.25(s,1H),2.24(s,1H),2.23(s,1H),2.07(s,2H),1.91(s,2H),1.67(s,2H),1.43(s,2H),1.40(s,2H). 13 C NMR(126MHz, CDCl3)δ169.50(s),136.58(s),126.67–126.36(m),123.09(s),122.22( s),119.69(s),119.00(s),116.20(s),111.32(s),63.77(s),58.29(s),58.55–58.01 (m),57.29(s),57.21(s),53.20(s),43.22(s),41.46(s),35.33(s),32.83(s),27.75 (s),27.14(s),26.45(s),21.17(s),20.76(s),18.96(s),18.43(s).LC-MS(ESI):m / z 430.9050[M+H]+.

[0095] Similarly, RO-B3 and RO-B7 were prepared using the above method.

[0096] RO-B7 12N-(5-methoxy-3-indolylmethyl)matrine methyl ester, light yellow solid, yield 67%, mp 61.8-62.9℃. 1H NMR (600MHz, CDCl3) δ7.22(t,J=7.9Hz,1H),6.99(s,1H),6.93(d,J=7.5Hz,1H),6.80(dd,J=8.1,2.3Hz,1H) ,4.22(d,J=13.4Hz,1H),3.80(s,3H),3.63(s,3H),3.32(d,J=13.4Hz,1H),3.03(s,1H),2.95(d,J=11.4Hz,1 H),2.76(dd,J=15.8,8.6Hz,1H),2.49(dd,J=11.8,4.0Hz,1H),2.31(td,J=6.6,2.1Hz,2H),2.25(s,1H),2. 03(d,J=2.4Hz,1H),2.01(s,3H),1.97(s,1H),1.92(s,1H),1.78(s,1H),1.71(d,J=2.6Hz,1H),1.47(s,1H). 13 C NMR(126MHz,DMSO)δ180.41(s),164.83(s),151.73(s),149.57(s),131.42(s) ,119.03(s),109.95(s),107.81(s),59.01(s),52.64(s),52.54(s),52.46(s) ,51.14(s),51.05(s),48.48(s),38.48(s),36.77(s),30.61(s),28.09(s),23 .00(s),22.38(s),21.70(s),16.42(s),16.01(s),14.19(s).LC-MS(ESI):m / z 464.3491[M+K]+.

[0097] Example 5

[0098] Preparation of compound RO-C1:

[0099]

[0100] Weigh 4.9g of benzoic acid and 3.65g of thiosemicarbazide in a 100mL round-bottom flask, add 10mL of 1,4-dioxane, stir at room temperature for 10min, add 14mL of phosphorus oxychloride under ice bath conditions, stir thoroughly for 0.5h, heat to reflux at 75°C, raise the temperature to 80°C, and react for 4h. After the reaction is completed, cool to room temperature, add 15mL to 16mL of ice water dropwise until the phosphorus oxychloride in the solution is completely neutralized, then filter the precipitated solid, wash twice with cold water, and dry the obtained solid to obtain the crude product of 2-amino-5-benzyl-1,3,4-thiadiazole, which is separated by silica gel column chromatography to obtain the pure product.

[0101] 2g of amino-5-benzyl-1,3,4-thiadiazole and 0.9mL of chloroacetyl chloride were reacted to obtain 2.7g of 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole, with a yield of 93.8%. 2.1g of methyl matrine and 6.3g of potassium carbonate were dissolved in 40mL of anhydrous acetonitrile, nitrogen was introduced, and stirred at room temperature to obtain a first reaction solution, and then 2.7g of 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole was dissolved in 10mL of acetonitrile, and added dropwise to the first reaction solution, stirred at room temperature, and after the reaction was complete, the solid was filtered and washed with ethyl acetate, the obtained liquid was extracted with deionized water, saturated brine was added, the obtained organic layer was dried with anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a pale yellow solid crude product, which was separated by silica gel column chromatography to obtain RO-C1 with a yield of 54%.

[0102] RO-C1 12N-N-(5-phenyl-1,3,4-thiadiazole)carbamoylmethylmatrine methyl ester, yellow-brown powder, yield 54%, mp 124.7-128.7℃. 1 H NMR(600MHz,DMSO)δ13.06(s,1H),7.96(s,1H),7.96(s,1H),7.95(s,1H),7.95(s,1H),7.54(s,1H),7.53(s ,1H),4.48(s,2H),3.34(s,7H),1.99(s,1H),1.33(s,1H),1.23(s,1H),1.17(t,J=7.1Hz,1H),0.86(s,1H). 13C NMR(125MHz,DMSO)δ174.06(s),173.44(s),166.27(s),153.50(s),132.91(s) ),132.70(s),128.84(s),126.61(s),67.56(s),63.05(s),57.59(s),54.68( s),53.21(s),51.87(s),40.87(s),37.98(s),33.71(s),29.06(s),28.28(s) ,26.40(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z498.8906[M+H]+.

[0103] RO-C2 to RO-C4 were synthesized using the above method and the following data were obtained.

[0104] RO-C2 12N-N-(5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole)carbamoylmethylmatrine methyl ester, white block solid, yield 47%, mp 191.2-195.2℃. 1 H NMR(600MHz,DMSO)δ7.92(s,1H),7.90(s,1H),7.56(s,1H),7.54(s,1H),5.25(s,1H),4.45(s,1 H),4.44(s,1H),4.36(s,3H),4.19(d,J=4.1Hz,1H),4.17(d,J=4.2Hz,1H),4.02(dd,J=14.3,7.1 Hz,1H),3.75(s,1H),2.95(s,2H),2.17(t,J=4.2Hz,1H),2.13(d,J=5.4Hz,1H),2.11(s,1H),2. 07(s,1H),1.98(s,1H),1.91(s,1H),1.82(d,J=13.9Hz,1H),1.56(d,J=7.6Hz,1H),1.55(s,2H). 13CNMR(126MHz,DMSO)δ174.06(s),173.44(s),166.27(s),154.50(s),152.65(s) ),139.64(s),127.27(s),106.22(s),67.56(s),63.05(s),60.70(s),57.59(s) ),56.83(s),54.68(s),53.33(s),51.87(s),40.87(s),37.94(s),33.71(s),2 9.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 588.8764[M+H]+.

[0105] RO-C3 12N-N-(5-(4-chlorophenyl)-1,3,4-thiadiazole)aminoacetylmatrine methyl ester, yellow-brown powder, yield 76%, mp 249.5-250.0℃. 1 H NMR(600MHz,DMSO)δ7.92(s,1H),7.90(s,1H),7.56(s,1H),7.54(s,1H),5.25(s,1H),4.45(s,1 H),4.44(s,1H),4.36(s,3H),4.19(d,J=4.1Hz,1H),4.17(d,J=4.2Hz,1H),4.02(dd,J=14.3,7.1 Hz,1H),3.75(s,1H),2.95(s,2H),2.17(t,J=4.2Hz,1H),2.13(d,J=5.4Hz,1H),2.11(s,1H),2. 07(s,1H),1.98(s,1H),1.91(s,1H),1.82(d,J=13.9Hz,1H),1.56(d,J=7.6Hz,1H),1.55(s,2H). 13 C NMR(151MHz,DMSO)δ174.06(s),173.44(s),166.27(s),153.50(s),137.52(s) ),131.68(s),128.45(s),128.01(s),67.56(s),63.05(s),57.59(s),54.68(s) ),53.21(s),51.87(s),40.87(s),37.94(s),33.71(s),29.06(s),28.28(s),2 6.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z548.6032[M+NH4]+.

[0106] RO-C4 12N-N-(5-(3-bromophenyl)-1,3,4-thiadiazole)aminoacetylmatrine methyl ester, yellow-brown powder, yield 74%, mp 162.2-163.4℃. 1 H NMR (600MHz, DMSO) δ7.98 (s, 1H), 7.96 (d, J = 4.1Hz, 1H), 7.95 (s, 1H), 7.95 (s, 1H), 7.45 (s, 2H), 7.4 0(s,2H),4.63(s,5H),3.62(s,15H),3.14(s,5H),2.62(d,J=5.9Hz,1H),2.60(s,1H),2.49(s,3H), 2.43(s,3H),2.35(s,4H),2.04(s,2H),1.98(s,2H),1.93(s,1H),1.82(s,1H),1.77(s,3H),1.72(s ,1H),1.63(s,2H),1.62(s,2H),1.53(s,1H),1.51(s,2H),1.45–1.45(m,2H),1.40(d,J=1.1Hz,1H). 13 C NMR(126MHz,DMSO)δ174.06(s),173.44(s),166.27(s),154.43(s),136.06(s) ,133.20(s),131.94(s),130.22(s),125.96(s),125.72(s),67.56(s),63.05(s) ),57.59(s),54.68(s),53.21(s),51.87(s),40.87(s),38.00(s),33.71(s),2 9.06(s),28.28(s),26.28(s),23.44(s),23.25(s),21.35(s).LC-MS(ESI):m / z 579.2796[M+Na]+.

[0107] The names and structural formulas of the target compounds synthesized above are shown in Table 1.

[0108] Table 1

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Application example: Anti-liver cancer and anti-lung cancer activity experiments were conducted on 32 target compounds synthesized

[0115] Solution preparation: Cell culture medium preparation: 1640 medium, 10wt% FBS (fetal bovine serum), 1wt% antibiotics, stored in a 4°C refrigerator. DMEM medium, 10wt% FBS, 1wt% antibiotics, stored in a 4°C refrigerator.

[0116] Preparation of cell freezing solution: 90wt% fetal bovine serum, 10wt% DMSO, prepared before use.

[0117] Preparation of MTT solution: Weigh 5 mg of MTT 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide and dissolve it in 1 mL of phosphate buffered saline (PBS). Shake it to dissolve, filter it with a 0.22 μm filter membrane to remove bacteria in the solution, and dispense it into 1.5 mL EP tubes and store it at -20°C away from light.

[0118] Compound sample preparation: Weigh matrine derivatives respectively and dissolve them in 1 mL DMSO (dimethyl sulfoxide) to prepare a sample solution with a concentration of 10 mM, and store it at -20°C in the dark.

[0119] Take out the cell culture bottle from the incubator, discard the original culture medium, rinse twice with PBS, remove the original culture medium and dead cells, and add 5mL new culture medium. First observe the growth state of the cells. When the cells in the culture bottle grow to about 90%, discard the original culture medium, rinse twice with PBS, add 2mL trypsin to digest the cells for 2 minutes, and observe the digested cells under an inverted microscope after trypsinization. The cytoplasm shrinks and becomes round, and the cells are no longer connected into pieces, indicating that the cells are moderately digested at this time. Add an equal amount of culture medium, gently blow the cells with a Pasteur pipette to make them fall, centrifuge at 1000r for 3min, discard the supernatant, add culture medium again, and gently blow the cells with a pipette to make a cell suspension, and place it in a 37℃, 5% CO2 incubator for sub-bottle culture. Take out the cancer cell line, quickly put the cryopreservation tube into a 37℃ water bath to thaw, transfer the cells in the cryopreservation tube into a 15mL centrifuge tube with a pipette, add 10mL cell culture medium to mix thoroughly, place in a centrifuge for 3 minutes, discard the supernatant after centrifugation, add 5mL cell culture medium to mix thoroughly, and inoculate into a new cell culture bottle, observe the cell growth status, and culture in a 37℃, 5% CO2 incubator.

[0120] The MTT method was used to determine the antitumor activity of matrine derivatives against human non-small cell lung cancer cell line A549 and human liver cancer cell line HepG-2. The experiment was repeated three times. The cancer cell lines were taken, the cells were revived and subcultured, and they grew to the logarithmic growth phase after 24 hours. The cells were digested with trypsin to make a cell suspension. 100 μL was inoculated into each well of a 96-well plate, and the edge wells were filled with sterile PBS. The 96-well cell culture plate was placed in a 37°C, 5% CO2 incubator for 24 hours, the culture medium was aspirated, and different derivatives were added for 48 hours. A blank control group, a control group, and a sample group (each group had 3 parallels) were set up. The blank culture group only added PBS without inoculating cells; the control group only added culture medium without derivative treatment; and the sample group added different concentrations of matrine derivatives. After the action of these derivatives, the adhesion state was observed under a microscope, and 10ul MTT solution was added under light-proof conditions to mix thoroughly, and the incubator continued to incubate for 4 hours. After the end, the culture medium in the cell plate was aspirated, and formazan formation could be seen in the cells. Add 100 μL DMSO to each well and place on a shaker for 10 minutes to fully dissolve the crystals. After the crystals are dissolved, place the 96-well plate in the specified direction into the microplate reader and measure the OD value at a wavelength of 490 nm using the microplate reader. Determine cell viability and calculate inhibition rate. Use survival rate = (sample group OD - blank group OD) / (control group OD - blank group OD)%, inhibition rate = 1 - survival rate, and use GraphPad to calculate drug IC 50 .

[0121] IC values ​​of target compounds against two tumor cells 50 The values ​​are shown in Table 2.

[0122] Table 2

[0123]

[0124]

[0125] The above experimental data show that, under the condition of using matrine as the control drug, all the synthesized 12-nitrogen-substituted matrine ester derivatives have good inhibitory activity against liver cancer cells HepG-2 and lung cancer cells A549, among which compounds RO-A13, RO-A18, RO-A19, RO-A21, RO-B4, RO-C1, RO-C3, and RO-C4 have good inhibitory effects on liver cancer cells HepG-2, and compounds RO-A3, RO-A5, RO-A13, RO-A18, RO-A19, RO-A21, RO-C1, RO-C3, and RO-C4 have good inhibitory effects on lung cancer cells A549. The above compounds all show good anti-tumor activity.

[0126] The embodiments described above are only descriptions of the preferred modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A 12-nitrogen substituted berberine acid ester derivative, characterized in that: The nitrogen at position 12 of matrine is connected by a carbon chain and then replaced by a benzene ring, or the nitrogen at position 12 of matrine is replaced by an aromatic heterocycle, or the nitrogen at position 12 of matrine is replaced by a phenylthiadiazolecarbamoylmethyl group; When the nitrogen at position 12 of matrine is connected by a carbon chain and then replaced by a benzene ring, the derivative is denoted as RO-A, and the structure is shown in general formula Ⅰ. In general formula I, RO-A5: R1 = R3 = H, R2 = Br, n = 1 RO-A9: R1 = R3 = H, R2 = CH3, n = 1 RO-A11: R2=H, R1=Br, R3=F, n=1 RO-A12: R3=H, R1=R2=F, n=1 RO-A13: R3=H, R1=F, R2=Br, n=1 RO-A15: R1=R2=R3=H, n=0 RO-A16: R2=R3=H, R1=NO2, n=0 RO-A18: R1=R3=H, R2=F, n=2 RO-A19: R1=R3=H, R2=CH3, n=2 RO-A20: R1=R2=R3=H, n=3 RO-A21: R1=R2=R3=H, n=4; When the nitrogen at position 12 of matrine is replaced by an aromatic heterocycle, the derivative is denoted as RO-B, and the structure is shown in general formula II. In general formula II, RO-B1: Ar = 2-quinolinemethyl RO-B2: Ar = 5-quinolinemethyl RO-B3: Ar = 3-quinolinylmethyl; When the nitrogen at position 12 of matrine is replaced by phenylthiadiazolecarbamoylmethyl, the derivative is denoted as RO-C, and the structure is shown in general formula III. In general formula III, 2. A method for preparing the 12-nitrogen substituted berberine acid ester derivative according to claim 1, characterized in that: The nitrogen at position 12 of methyl matrine is substituted with different groups, comprising the following steps: Dissolve methyl matrine and potassium carbonate in anhydrous acetonitrile, introduce nitrogen, and stir at room temperature to obtain a first reaction solution. Dissolve 2-chlorobenzyl bromide in acetonitrile and add dropwise to the first reaction solution. Stir at room temperature. After the reaction is complete, filter the solid and rinse the solid with ethyl acetate. Extract the obtained liquid with deionized water, add saturated brine, dry the obtained organic layer with anhydrous sodium sulfate, and concentrate by rotary evaporation to obtain a pale yellow solid crude product. Separate it by silica gel column chromatography to obtain a derivative RO-A1. Synthesize RO-A5, RO-A9, RO-A11 to RO-A13, RO-A18 to RO-A19, RO-B1, RO-B2 to RO-B3 by referring to the above method. Methyl matrine was dissolved in anhydrous methanol, nitrogen was introduced, and the mixture was stirred at room temperature. Lithium aluminum hydride was dissolved in anhydrous methanol under ice bath conditions to obtain a first reaction solution. Bromobenzene was dissolved in anhydrous methanol, and the methanol solution containing bromobenzene was added dropwise to the first reaction solution. The mixture was stirred at room temperature. After the reaction was complete, derivative RO-A15 was obtained. Derivative RO-A16 was synthesized by referring to the above method. Dissolve triphenylphosphine and tetrabutylammonium bromide in dichloromethane, stir at room temperature, then drop phenylpropanol, reflux at 120°C for 0.5h to 1h, and after the reaction is completed, separate by silica gel column chromatography to obtain an intermediate product 1-bromo-3-phenylpropane; referring to the above method, add phenylbutanol to a mixed system of triphenylphosphine and tetrabutylammonium bromide to obtain an intermediate product 1-bromo-4-phenylbutane, react the above-obtained 1-bromo-3-phenylpropane and 1-bromo-4-phenylbutane with methyl berberine, respectively, and refer to the above method for synthesizing RO-A1 to obtain derivatives RO-A20 and RO-A21; Benzoic acid and thiosemicarbazide were dissolved in 1,4-dioxane solution, stirred at room temperature, and then phosphorus oxychloride was added in an ice bath. After sufficient stirring, the mixture was heated to reflux at 75-80°C for 4-6 hours. After the reaction was completed, the mixture was cooled to room temperature, and ice water was added in batches until the phosphorus oxychloride in the solution was completely neutralized. The precipitated solid was then filtered and washed twice with cold water. The obtained solid was dried to obtain a crude intermediate product 2-amino-5-phenyl-1,3,4-thiadiazole. The pure product was separated by silica gel column chromatography. 2 g of 2-amino-5-phenyl-1,3,4-thiadiazole was weighed and reacted with 0.9 mL of chloroacetyl chloride to obtain 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole. Then, referring to the synthesis method of derivative RO-A1, 2-chloroacetylamino-5-phenyl-1,3,4-thiadiazole and methyl matrine were reacted to obtain derivatives RO-C1 to RO-C4.

3. The method for preparing the 12-nitrogen substituted berberine acid ester derivative according to claim 2, characterized in that: The preparation method of methyl berberine is as follows: dissolving matrine in sodium hydroxide solution, refluxing at 120° C. for 8 to 9 hours, cooling to room temperature after complete reaction, precipitating white crystals, filtering and dissolving with concentrated hydrochloric acid, concentrating the obtained solution to obtain a white solid, drying to obtain matrine, dissolving matrine in anhydrous methanol, adding dichlorothionyl dropwise under ice bath conditions, stirring at room temperature, refluxing at 70 to 80° C. for 5 to 7 hours, cooling to room temperature after complete reaction, concentrating, adding methanol solution for washing and concentrating, repeating washing and concentrating 3 to 5 times, and drying to obtain methyl berberine.

4. The method for preparing the 12-nitrogen substituted berberine acid ester derivative according to claim 3, characterized in that: The solid-liquid ratio of matrine to thionyl chloride is (10 g-15 g): (12 mL-15 mL).

5. The method for preparing the 12-nitrogen substituted berberine acid ester derivative according to claim 2, characterized in that: When synthesizing derivative RO-A15, the solid-liquid ratio of methyl berberine, lithium aluminum hydride and bromobenzene is 2g:0.68g:0.64mL.

6. The method for preparing the 12-nitrogen substituted berberine acid ester derivative according to claim 2, characterized in that: When synthesizing the derivative RO-A20, the mass ratio of triphenylphosphine to tetrabutylammonium bromide is 1.57:2.22; the polarity of the eluent is: V 石油醚 :V 乙酸乙酯 =3∶1~1∶1.

7. Use of the 12-nitrogen substituted matrine derivative according to claim 1 in the preparation of drugs for preventing and / or treating liver cancer and lung cancer.

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