CN110117307B

CN110117307B - Aralia saponin derivative and preparation method and application thereof

Info

Publication number: CN110117307B
Application number: CN201910223031.6A
Authority: CN
Inventors: 田瑜; 许旭东; 孙桂波; 孙晓波; 尚海
Original assignee: Institute of Medicinal Plant Development of CAMS and PUMC
Current assignee: Institute of Medicinal Plant Development of CAMS and PUMC
Priority date: 2019-03-22
Filing date: 2019-03-22
Publication date: 2020-08-04
Anticipated expiration: 2039-03-22
Also published as: CN110117307A

Abstract

The invention discloses an araloside derivative, a preparation method and application thereof, wherein the araloside derivative has a structure shown in a general formula (I). The invention takes oleanolic acid and four kinds of sugar, caffeic acid or 3-methoxy 4-hydroxycinnamic acid as raw materials, keeps the structural skeleton of oleanolic acid, carries out glycosylation modification on the hydroxyl group on the 3-position of the oleanolic acid, and modifies 28-position carboxyl, thereby synthesizing the novel araloside derivative with the functions of treating cardiovascular and cerebrovascular diseases and the like, and the synthesis method is simple and convenient and the product purity is high. Compared with Aralia elata monomer saponin, the Aralia elata saponin derivative provided by the invention has the following advantages: 1. the source is easy to obtain, and the synthesis is simple and convenient; 2. has better biological activity and solubility compared with the prototype; 3. the structure is brand new.

Description

Aralia saponin derivative and preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry and therapeutics, in particular to an araloside derivative, a preparation method and application thereof.

Background

Aralia elata (Aralia elata Seem) is also called Aralia elata (Aralia elata Seem), which is called Aralia elata (L.) Seem in folk, and is perennial deciduous shrub of Aralia in Araliaceae. There are a total of forty species of aralia genus in araliaceae worldwide, and they are mainly distributed in the far east and continental americas. There are about thirty kinds of Aralia elata in continental China, and the Aralia elata is mainly distributed in northeast China.

Aralia elata seem is a plant with homology of medicine and food, and its inner bud is often used as a food material by folks. As early as the year of Song dynasty, there are cases in China where root bark of Aralia elata seem is used as guiding drug, and as early as the year of first Tang dynasty, root and bark of Aralia elata seem are often used as guiding drug in folks, which is called Aralia mandshurica. At the beginning of building the country, Aralia elata and Aralia elata belong to two different plants, but the difference of the external characteristics is very small, and later researchers are used to classify the Aralia elata and the Aralia elata into one class. Modern researches show that the root, stem and leaf of Aralia elata seem contain abundant chemical active ingredients, have wide pharmacological effects, and can be used for treating myocardial infarction, arthritis, myocardial infarction, gastric ulcer, neurasthenia and the like.

The chemical components separated from root, stem and leaf of Aralia elata seem mainly include saponin and flavonoid, and also include fat, saccharide, aromatic oil, volatile oil, protein, amino acid, inorganic elements, etc.

Aralia saponin is a chemical component with the most content in the root and stem of Aralia elata, and the variety of aralia elata saponin is more than hundred. The aglycone of araloside is mainly pentacyclic triterpenoid such as oleanolic acid, ursolic acid, Paeonia lactiflora and ivy, and these pentacyclic triterpenoids are easily connected with saccharide at C-3 or C-28 position to form glycoside, and the saccharide mainly comprises D-glucose (D-glucose) and D-galactose (D-galactose).

The aralia elates total saponins have protective effects on isoproterenol-induced myocardial ischemia injury and rat cardiac infarction caused by coronary artery ligation; in addition, the Aralia elata total saponins can slow down the frog heart rate and increase the amplitude, and positive inotropic effect appears in vitro frog heart experiments.

Earlier researches show that triterpenoid saponin components in Aralia elata seem have the purpose of treating coronary heart disease and angina pectoris, and the traditional Chinese Aralia heart meridian dredging capsules taking Aralia saponin as a main component have already obtained a pharmaceutical clinical research batch and completed clinical observation.

Although oleanolic acid-3-O- β -D-glucopyranose-uronic acid is a natural product having good biological activity, it has some disadvantages in that its plant source is limited as a natural product, and its activity level is relatively weak compared to chemical drugs and has a problem in solubility although it has various biological activities.

Disclosure of Invention

In view of the above, the invention aims to provide an araloside derivative, a preparation method and an application thereof, which solve the problem of limited natural plant sources and simultaneously improve the problem of weak effect of araloside.

Based on the purpose, the invention provides an araloside derivative which has a structure shown in a general formula (I):

in the formula: r₁、R₂、R₃、R₄、R₅And R₆Each independently selected from H or OH;

R₇is selected from H or CH₂OH；

R₈Is selected from H or CH₃；

R₉Selected from OH or OCH₃。

In some embodiments of the invention, R₁And R₂In a different sense, R₃And R₄In a different sense, R₅And R₆Different.

In some embodiments of the invention, the araloside derivatives are compounds M1-M4 and N1-N4 shown in the following structural formula,

in the compound M1, R₁＝OH，R₂＝H，R₃＝H，R₄＝OH，R₅＝OH，R₆＝H，R₇＝CH₂OH，R₈＝H，R₉＝OH；

In the compound M2, R₁＝OH，R₂＝H，R₃＝OH，R₄＝H，R₅＝H，R₆＝OH，R₇＝H，R₈＝CH₃，R₉＝OH；

In the compound M3, R₁＝OH，R₂＝H，R₃＝H，R₄＝OH，R₅＝OH，R₆＝H，R₇＝H，R₈＝H，R₉＝OH；

In the compound M4, R₁＝H，R₂＝OH，R₃＝OH，R₄＝H，R₅＝OH，R₆＝H，R₇＝H，R₈＝H，R₉＝OH；

In the compound N1, R₁＝OH，R₂＝H，R₃＝H，R₄＝OH，R₅＝OH，R₆＝H，R₇＝CH₂OH，R₈＝H，R₉＝OCH₃；

In the compound N2, R₁＝OH，R₂＝H，R₃＝OH，R₄＝H，R₅＝H，R₆＝OH，R₇＝H，R₈＝CH₃，R₉＝OCH₃；

In the compound N3, R₁＝OH，R₂＝H，R₃＝H，R₄＝OH，R₅＝OH，R₆＝H，R₇＝H，R₈＝H，R₉＝OCH₃；

In the compound N4, R₁＝H，R₂＝OH，R₃＝OH，R₄＝H，R₅＝OH，R₆＝H，R₇＝H，R₈＝H，R₉＝OCH₃。

The invention also provides a preparation method of the araloside derivative, which comprises the following steps:

reacting oleanolic acid with benzyl bromide under the action of organic base to obtain an intermediate S1;

the intermediate S1 reacts with the intermediates D1-D4 respectively to obtain intermediates F1-F4;

at H₂Under the action of palladium carbon, intermediates F1-F4 are respectively reduced to obtain intermediates G1-G4;

the intermediates G1-G4 react with 1-amino-11-azido-3, 6, 9-trioxaundecane respectively to obtain intermediates I1-I4;

the intermediates I1-I4 respectively react with sodium methoxide methanol solution to obtain intermediates L1-L4;

in intermediate F1, intermediate G1 and intermediate I1, R₁＝OBz，R₂＝H，R₃＝H，R₄＝OBz，R₅＝OBz，R₆＝H，R₇＝CH₂OBz，R₈＝H；

In intermediate F2, intermediate G2 and intermediate I2, R₁＝OBz，R₂＝H，R₃＝OBz，R₄＝H，R₅＝H，R₆＝OBz，R₇＝H，R₈＝CH₃；

In intermediate F3, intermediate G3 and intermediate I3, R₁＝OBz，R₂＝H，R₃＝H，R₄＝OBz，R₅＝OBz，R₆＝H，R₇＝H，R₈＝H；

In intermediate F4, intermediate G4 and intermediate I4, R₁＝H，R₂＝OBz，R₃＝OBz，R₄＝H，R₅＝OBz，R₆＝H，R₇＝H，R₈＝H。

R in intermediate L1-L4₁～R₈The substituent and the corresponding R in the compounds M1-M4 or N1-N4₁～R₈The substituents are the same.

Caffeic acid or 3-methoxy-4-hydroxycinnamic acid reacts with propargylamine respectively to obtain intermediates P1-P2;

the intermediate P1 reacts with the intermediates L1-L4 respectively to obtain saponin derivatives M1-M4;

the intermediate P2 reacts with the intermediates L1-L4 respectively to obtain saponin derivatives N1-N4;

in some embodiments of the invention, intermediates D1-D4 are prepared using the following method:

reacting the monosaccharide with benzoyl chloride to obtain an intermediate A1-A4;

the intermediates A1-A4 react with cyanogen bromide acetic acid solution respectively to obtain intermediates B1-B4;

the intermediates B1-B4 react with water and silver oxide respectively to generate intermediates C1-C4;

the intermediates C1-C4 react with trichloroacetonitrile respectively to generate intermediates D1-D4;

the general formulas of D1-D4 are:

in intermediate D1, R₁＝OBz，R₂＝H，R₃＝H，R₄＝OBz，R₅＝OBz，R₆＝H，R₇＝CH₂OBz，R₈＝H；

In intermediate D2, R₁＝OBz，R₂＝H，R₃＝OBz，R₄＝H，R₅＝H，R₆＝OBz，R₇＝H，R₈＝CH₃；

In intermediate D3, R₁＝OBz，R₂＝H，R₃＝H，R₄＝OBz，R₅＝OBz，R₆＝H，R₇＝H，R₈＝H；

In intermediate D4, R₁＝H，R₂＝OBz，R₃＝OBz，R₄＝H，R₅＝OBz，R₆＝H，R₇＝H，R₈＝H。

The synthetic route of intermediate D1 is as follows:

the synthetic route of intermediate D2 is as follows:

the synthetic route of intermediate D3 is as follows:

the synthetic route of intermediate D4 is as follows:

in some embodiments of the invention, oleanolic acid is dissolved in methylene chloride and tetrabutylammonium bromide and K are added sequentially₂CO₃Stirring the solution for 20-40 minutes, dropwise adding benzyl bromide at 0 ℃, and stirring for 1-3 days at room temperature to obtain an intermediate S1;

respectively dissolving the intermediate S1 and the intermediates D1-D4 with dichloromethane, adding a powdery 4A molecular sieve, reacting for 0.5-1.5 hours at room temperature under the protection of nitrogen, then adding a catalytic amount of trimethylsilyl trifluoromethanesulfonate, and continuing to react for 1.5-2.5 hours to obtain intermediates F1-F4;

dissolving the intermediates F1-F4 in ethyl acetate respectively, introducing nitrogen for 4-6 minutes, introducing hydrogen, adding a palladium-carbon catalyst, and heating and refluxing for 1-3 hours at 40-50 ℃ to obtain intermediates G1-G4;

respectively dissolving the intermediates G1-G4 by using dichloromethane, adding 1-hydroxybenzotriazole and carbodiimide, stirring for 0.5-1.5h at room temperature, dropwise adding 1-amino-11-azido-3, 6, 9-trioxaundecane at 0 ℃, and continuously reacting for 3-5 h at room temperature to obtain intermediates I1-I4;

dissolving the intermediates I1-I4 in a mixed solution of dry methanol and dry dichloromethane respectively, adding a sodium methoxide methanol solution, and reacting for 1-3 hours at room temperature to obtain intermediates L1-L4;

dissolving caffeic acid or 3-methoxy-4-hydroxycinnamic acid with N, N-dimethylformamide, and adding triethylamine to obtain N, N-dimethylformamide mixed solution; dissolving benzotriazole-1-oxytris (dimethylamino) phosphorus hexafluorophosphate in dichloromethane, and dropwise adding propargylamine at 0 ℃ to obtain a propargylamine mixed solution; dropwise adding the propargylamine mixture into the N, N-dimethylformamide mixture, reacting for 20-40 minutes at 0 ℃, and then reacting for 1-3 hours at room temperature to obtain intermediates P1-P2;

dissolving the intermediate P1 with methanol, adding a catalyst of thiophene-2-copper formate, then respectively adding the intermediates L1-L4, and stirring overnight at room temperature to obtain saponin derivatives M1-M4;

dissolving the intermediate P2 with methanol, adding a catalyst of thiophene-2-copper formate, then respectively adding the intermediates L1-L4, and stirring overnight at room temperature to obtain saponin derivatives N1-N4.

reacting monosaccharide with benzoyl chloride for 15-20 hours at room temperature to obtain intermediates A1-A4;

reacting the intermediates A1-A4 with 33% (mass fraction) cyanogen bromide acetic acid solution at room temperature for 1-3 hours to obtain intermediates B1-B4;

dissolving the intermediates B1-B4 in acetone, adding water and silver oxide, and reacting for 3-5 hours at room temperature to obtain intermediates C1-C4;

dissolving the intermediates C1-C4 by using dioxymethane, adding trichloroacetonitrile and 1, 8-diazabicycloundecen-7-ene, and reacting for 3-5 hours at room temperature to obtain the intermediates D1-D4.

In some embodiments of the invention, the monosaccharide is selected from one of glucose, rhamnose, xylose or arabinose.

The invention also provides a pharmaceutical composition, which comprises the araloside derivative and a medicinal carrier.

The invention also provides the application of the araloside derivative in preparing the medicaments for protecting the cardiovascular and cerebrovascular diseases.

From the above, the invention takes oleanolic acid and four kinds of sugar, caffeic acid or 3-methoxy 4-hydroxycinnamic acid as raw materials, the structural skeleton of the oleanolic acid is kept, the hydroxyl group on the 3-position of the oleanolic acid is aligned for glycosylation modification, and the 28-position carboxyl is modified, so that the novel araloside derivative with the functions of treating cardiovascular and cerebrovascular diseases and the like is synthesized, the synthesis method is simple and convenient, and the product purity is high. Compared with Aralia elata monomer saponin, the Aralia elata saponin derivative provided by the invention has the following advantages: 1. the source is easy to obtain, and the synthesis is simple and convenient; 2. has better biological activity and solubility compared with the prototype; 3. the structure is brand new.

Drawings

FIGS. 1a to 1h are the biological activity diagrams of compounds M1 to M4 and N1 to N4, respectively; wherein, control refers to blank group, i.e. H9c2 cells which are not administrated and are not induced by hypoxia reoxygenation; model refers to H9c2 cells that were not administered, but were induced by hypoxia-reoxygenation; CE refers to Aralia chinensis monomer saponin pre-administration, and then H9c2 cells induced by hypoxia reoxygenation; 0.02 mu M refers to the pre-adding of 0.02 mu M compounds M1-M4 and N1-N4 respectively, and then H9c2 cells induced by hypoxia reoxygenation; 0.1 mu M refers to that 0.1 mu M of compounds M1-M4 and N1-N4 are added in advance, and then H9c2 cells are induced by hypoxia reoxygenation; 0.5. mu.M means that 0.5. mu.M of the compounds M1-M4 and N1-N4 were pre-added, followed by hypoxia-reoxygenation-induced H9c2 cells.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below.

EXAMPLE 1 preparation of Compound M1

(1) Preparation of intermediate D1

The synthetic route of intermediate D1 is as follows:

① Synthesis of intermediate A1

Accurately weighing glucose (5.0g, 27.7mmol), adding the glucose into a 500m L round-bottom flask, dissolving the glucose with 100m L redistilled pyridine, adding benzoyl chloride (18.0m L, 171.2mmol) at the temperature of 0 ℃, stirring the reaction solution at the temperature of a reaction solution room for 18 hours, monitoring the reaction at T L C, adding petroleum ether-ethyl acetate (3: 1) as a developing agent, performing after-treatment, adding distilled water 60m L and 500m L to a separating funnel to extract an organic phase, then sequentially washing the organic phase with 1N hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution for 3 times, drying the organic layer with anhydrous sodium sulfate for 2 hours, performing suction filtration, and concentrating the organic layer under reduced pressure to obtain a white crude solid A1, A1: 17.3g and 89.17 percent of yield.

② Synthesis of intermediate B1

Accurately weighing intermediate A1(16.1g, 23.0mmol), adding into a 500m L round-bottom flask, dissolving with 200m L dry dichloromethane, dropwise adding 33% (mass fraction) acetic acid bromide solution 30m L at 0 ℃, stirring the reaction solution at room temperature for 2 hours, monitoring the reaction by T L C, adjusting the pH of the reaction solution to be neutral by using a saturated sodium bicarbonate solution, extracting an organic layer, washing the organic layer for 3 times by using a saturated sodium carbonate solution and a saturated sodium chloride solution, drying the organic layer by using anhydrous sodium sulfate, filtering, and concentrating the organic layer under reduced pressure to obtain a white crude solid B1, B1: 13.4g, wherein the yield is 88.74%.

③ Synthesis of intermediate C1

Accurately weighing intermediate B1(13.2g, 20.0mmol), adding the intermediate B1 into a 500m L round-bottom flask, dissolving the intermediate B1 in acetone with the thickness of 100m L, adding 13.2m L water and 6.5g of silver oxide, stirring the reaction solution at room temperature for 4 hours, monitoring the reaction by T L C, performing suction filtration by using a developing agent petroleum ether-ethyl acetate (4: 1), and evaporating the filtrate under reduced pressure to dryness to obtain a crude white solid C1, C1: 9.2g and the yield of 77.25%.

④ Synthesis of intermediate D1

Intermediate C1(9.0g, 15.0mmol) was weighed accurately into a round bottom flask, dissolved in 100m L dry dichloromethane, trichloroacetonitrile (8.9m L, 90mmol), DBU (1, 8-diazabicycloundecen-7-ene, 0.93m L, 6mmol) were added and the reaction solution was allowed to stand at room temperature for 4h, monitored at T L C for reaction, worked up with petroleum ether-ethyl acetate (5: 1) as developing solvent, saturated sodium bicarbonate solution, saturated anhydrous sodium chloride solution washed 3 times, sodium sulfate dried overnight, the organic layer filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, petroleum ether-ethyl acetate (8: 1) eluted to give D1, D1: 6.8g, 60.71% yield as a white solid.

(2) Synthesis of intermediate S1

Oleanolic acid (20g, 43.8mmol) was added to a 500M L round bottom flask, dissolved with 400M L dichloromethane, and tetrabutylammonium bromide (1.6g, 4.9mmol) and 0.8M K were added to the round bottom flask in sequence₂CO₃The solution was stirred for 30 minutes, benzyl bromide (6.44m L, 54.3mmol) was slowly added dropwise at 0 ℃, after the addition was complete, the reaction solution was stirred at room temperature for about 2 days, the reaction was complete as a sign of disappearance and stratification of the white solid in the solution, T L C detection reaction (color development of phosphomolybdic acid required), petroleum ether-ethyl acetate (4: 1), post-treatment, the organic layer was washed 3 times with saturated sodium bicarbonate solution, saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, the residue was purified by silica gel column chromatography, and petroleum ether-ethyl acetate (8: 1) was eluted to give a white solid, S1, S1: 18.5g, yield 77.08%.

(3) Synthesis of intermediate F1

Accurately weighing the intermediates S1(3.3g and 6.0mmol) and D1(5.8g and 7.9mmol), adding the intermediates into a 100m L round-bottom flask, dissolving 50m L of anhydrous dichloromethane, adding 5g of powdery 4A molecular sieve, stirring the reaction solution at room temperature for 1h under the protection of nitrogen, then adding a catalytic amount of trimethylsilyl trifluoromethanesulfonate (60 mu L and 0.3mol), continuing to react for 2h, monitoring the reaction by T L C, adding 1.0m L of triethylamine to quench the reaction after the reaction is finished, filtering to remove the molecular sieve, evaporating the filtrate under reduced pressure, purifying the residue by silica gel column chromatography, eluting by petroleum ether-ethyl acetate (10: 1), and obtaining a white solid F1, F1: 7.1g and yield of 80.68%.

(4) Synthesis of intermediate G1

F1(3.4G, 3.0mmol) is added into a 100m L round-bottom flask, 100m L ethyl acetate is dissolved, one side of a three-necked flask is inserted into a thermometer to monitor the reaction temperature, nitrogen starts to be introduced into the other side, 5 minutes later, the introduced nitrogen is changed into hydrogen, 2G of Pd-C catalyst is added, the reaction is monitored by heating and refluxing at 45 ℃ and about 2 h.T L ℃, after the reaction is completed, the reaction solution is filtered while hot, washed by hot ethyl acetate, concentrated under reduced pressure, purified by silica gel column chromatography, and eluted by petroleum ether-ethyl acetate (3: 1) to obtain white solid G1, G1: 2.5G, and the yield is 80.13%.

(5) Synthesis of intermediate I1

Intermediate G1(1.50G, 1.45mmol) was weighed accurately into a 100m L round bottom flask, dissolved in 15m L anhydrous dichloromethane, followed by the addition of HOBT (1-hydroxybenzotriazole, 0.20G, 1.45mmol) and EDCI (carbodiimide, 0.28G, 1.45mmol), the reaction solution was stirred at 0 ℃ for 1h, 1-amino-11-azido-3, 6, 9-trioxaundecane (8mmol) was added dropwise at 0 ℃, the reaction was continued at 4 h.T L C at 0 ℃ to monitor the reaction, the developing agent was petroleum ether-ethyl acetate (5: 1) post-treatment, the pH was adjusted to below 7 with 1N hydrochloric acid, the organic layer was extracted with dichloromethane, the saturated aqueous sodium bicarbonate solution, the saturated aqueous sodium chloride solution was washed three times, dried over anhydrous sodium sulfate overnight, suction filtered, the filtrate was evaporated to dryness under reduced pressure, the residue was purified by silica gel column chromatography, eluted with petroleum ether-ethyl acetate (8: 1) to give a white solid, I1, I1: 1.24, yield, 38.38.

(6) Synthesis of intermediate L1

Intermediate I1(536mg, 0.5mmol) is accurately weighed and added into a 100m L round bottom flask, 5m L dry methanol and 2.5m L dry dichloromethane are dissolved (the volume ratio of the two is 2:1), 2m L sodium methoxide methanol solution (1 mol/L) is added, the reaction solution is stirred at the temperature of the reaction solution room for 2 h.T L C to monitor the reaction, a developing agent is dichloromethane-methanol (8: 1), the post-treatment is carried out, the pH is adjusted to be neutral by activated cation exchange resin, the reaction solution is filtered, reduced pressure is evaporated to dryness, the residue is purified by silica gel column chromatography, and dichloromethane-methanol (10: 1) is eluted to obtain white powder L1, L1: 261mg, and the yield is 76.76%.

(7) Synthesis of intermediate P1

Accurately weighing caffeic acid (180mg, 1mmol), adding into a 50M L round bottom flask, adding 2M L DMF (N, N-dimethylformamide) for dissolving, adding 0.14M L triethylamine, accurately weighing BOP (benzotriazole-1-oxytris (dimethylamino) phosphonium hexafluorophosphate, 442.3mg, 1mmol) for dissolving in 2M L dichloromethane, dropwise adding propargylamine (1mmol) at 0 ℃, slowly dropwise adding the mixture into the DMF mixture, stirring the mixture at 0 ℃ for 30min, stirring the reaction solution at room temperature for 2 h.T L C for detecting reaction, after the reaction is finished, concentrating the solvent under reduced pressure, diluting with 15M L water, extracting with ethyl acetate, sequentially adding 1NHCl, distilled water and 1M NaHCO₃And a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with methylene chloride-methanol (35: 1) to give P1 as a pale yellow solid. P1: 186.22mg, yield 85.73%.

(8) Synthesis of Compound M1

P1(50mg, 0.19mmol) was weighed accurately and added to a 50M L round bottom flask, 2M L methanol was added to dissolve, thiophene-2-copper formate (3.6mg,0.019mmol) catalyst was added, intermediate L1 (155.6mg, 0.19mmol) was added, the reaction solution was stirred overnight at room temperature, T L C monitored for reaction, dichloromethane-methanol-water (50: 10: 1) was used as a developing agent, 365nm product was fluorescent and iodine developed, the reaction solution was filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and dichloromethane-methanol (6: 1) was eluted to give M1 as a white powder.

¹H-NMR(600MHz,pyridine-d₅):9.43(t,J＝5.4Hz,1H,N”-H),8.15(s,1H,Triazole-H),8.10(d,J＝15.5Hz,1H,H-7′’),7.55-7.53(m,2H,H-2′’,N-H),7.19-7.14(m,1H,H-5′’,6”),6.88(d,J＝15.6Hz,1H,H-8′’),5.46(t,J＝3.3Hz,1H,H-12),4.97(d,J＝5.7Hz,2H,H-10′’),4.95(d,J＝7.8Hz,1H,H-1’),4.61-4.59(m,1H,H-2’),4.55(t,J＝5.2Hz,2H,H-38),4.44-4.41(m,1H,H-5’),4.29-4.22(m,2H,H-6’),4.07-4.01(m,2H,H-3’,4’),3.80(t,J＝5.2Hz,2H,H-37),3.77-3.53(m,12H,H-31～36),3.39(dd,J＝11.8,4.4Hz,1H,H-3),3.07(dd,J＝13.0,3.8Hz,1H,H-18),1.32(s,3H,CH₃),1.27(s,3H,CH₃),1.02(s,3H,CH₃),0.94(s,3H,CH₃),0.93(s,3H,CH₃),0.91(s,3H,CH₃),0.88(s,3H,CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.7,166.7,149.4,147.5,146.0,144.6,141.0,127.5,123.7,122.7,121.1,118.7,116.6,115.2,106.8,88.7,78.6,78.2,75.6,71.6,70.7,70.5,70.4,70.0,69.5,62.9,55.6,50.1,47.8,46.6,46.3,42.0,41.7,39.7,39.6,39.4,38.5,36.8,35.5,34.2,33.5,33.1,32.8,30.7,28.1,27.7,26.4,26.0,23.7,23.6,23.5,18.3,17.2,16.9,15.4；HRMS(ESI):Calcd for[M+Na]⁺C₅₆H₈₅N₅NaO₁₃:1058.6042,found 1058.6118.

EXAMPLE 2 preparation of Compound M2

In this embodiment, the intermediate D2 is obtained by using rhamnose as a raw material through steps ① to ④ which are the same as those in embodiment 1;

the same step (2) as in example 1 is adopted, and oleanolic acid is taken as a raw material to obtain an intermediate S1;

the same step (3) as in example 1 was employed, intermediate S1 and intermediate D2 reacted to give intermediate F2;

intermediate F2 using the same steps (4) to (6) as example 1 gave intermediate L2;

the same procedure (7) as in example 1 was followed, caffeic acid was reacted with propargylamine to give intermediate P1;

(8) synthesis of Compound M2

P1(50mg, 0.19mmol) was weighed accurately and added to a 50M L round bottom flask, 2M L methanol was added to dissolve, thiophene-2-copper formate (3.6mg,0.019mmol) catalyst was added, intermediate L2 (152.6mg, 0.19mmol) was added, the reaction solution was stirred overnight at room temperature, T L C monitored for reaction, dichloromethane-methanol-water (50: 10: 1) was used as a developing agent, 365nm product was fluorescent and iodine developed, the reaction solution was filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and dichloromethane-methanol (6: 1) was eluted to give M2 as a white powder.

¹H-NMR(600MHz,pyridine-d₅):9.45(t,J＝5.3Hz,1H,N”-H),8.17(s,1H,Triazole-H),8.11(d,J＝15.5Hz,1H,H-7′’),7.56-7.53(m,2H,H-2′’,N-H),7.19-7.15(m,1H,H-5′’,6”),6.89(d,J＝15.6Hz,1H,H-8′’),5.47(t,J＝3.3Hz,1H,H-12),4.99(d,J＝5.6Hz,2H,H-10′’),5.33(m,1H,H-1’),4.59-4.58(m,1H,H-2’),4.56(t,J＝5.2Hz,2H,H-38),4.51-4.49(m,1H,H-5’),4.37-4.30(m,2H,H-3’,4’),3.82(t,J＝5.2Hz,2H,H-37),3.77-3.57(m,12H,H-31～36),3.16(dd,J＝11.6,4.1Hz,1H,H-3),3.08(dd,J＝13.1,3.5Hz,1H,H-18),1.68(d,J＝5.6Hz,3H,H-6’),1.26(s,3H,CH₃),0.96(s,3H,CH₃),0.93(s,3H,CH₃),0.92(s,3H,CH₃),0.91(s,3H,CH₃),0.90(s,3H,CH₃),0.82(s,3H,CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.7,166.6,149.3,147.4,146.0,144.5,140.9,127.4,123.7,122.6,121.0,118.7,116.5,115.1,104.2,88.2,73.9,72.7,72.3,70.6,70.4,70.4,70.0,69.7,69.4,62.9,55.3,50.0,47.7,46.5,46.3,42.0,41.6,39.7,39.5,38.9,38.3,36.7,35.4,34.2,33.5,33.0,32.7,30.7,28.0,27.6,25.9,25.6,23.6,23.5,23.5,18.3,17.1,16.5,15.3；HRMS(ESI):Calcd for[M+Na]⁺C₅₆H₈₅N₅NaO₁₂:1042.6092,found1042.6158.

EXAMPLE 3 preparation of Compound M3

In this example, the same steps ① - ④ as in example 1 were used to obtain intermediate D3 starting from xylose;

the same step (3) as in example 1 was employed, intermediate S1 and intermediate D3 reacted to give intermediate F3;

intermediate F3 using the same steps (4) to (6) as example 1 gave intermediate L3;

(8) synthesis of Compound M3

P1(50mg, 0.19mmol) was weighed accurately and added to a 50M L round bottom flask, 2M L methanol was added to dissolve, thiophene-2-copper formate (3.6mg,0.019mmol) catalyst was added, intermediate L3 (149.9mg, 0.19mmol) was added, the reaction solution was stirred overnight at room temperature, T L C monitored for reaction, dichloromethane-methanol-water (50: 10: 1) was used as a developing agent, 365nm product was fluorescent and iodine developed, the reaction solution was filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and dichloromethane-methanol (6: 1) was eluted to give M3 as a white powder.

¹H-NMR(600MHz,pyridine-d₅):9.45(t,J＝5.4Hz,1H,N”-H),8.16(s,1H,Triazole-H),8.10(d,J＝15.5Hz,1H,H-7′’),7.55-7.53(m,2H,H-2′’,N-H),7.19-7.14(m,1H,H-5′’,6”),6.88(d,J＝15.5Hz,1H,H-8′’),5.46(t,J＝3.3Hz,1H,H-12),4.98(d,J＝5.4Hz,2H,H-10′’),4.85(d,J＝7.5Hz,1H,H-1’),4.55(t,J＝5.1Hz,2H,H-38),4.41-4.38(m,1H,H-2’),4.27-4.17(m,2H,H-5’),4.05-4.02(m,1H,H-3’),3.81-3.78(m,3H,H-4’,H-37),3.78-3.55(m,12H,H-31～36),3.36(dd,J＝11.7,4.0Hz,1H,H-3),3.08(dd,J＝13.0,3.5Hz,1H,H-18),1.32(s,3H,CH₃),1.27(s,3H,CH₃),1.01(s,3H,CH₃),0.95(s,3H,CH₃),0.93(s,3H,CH₃),0.92(s,6H,2×CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.7,166.7,149.4,147.5,146.0,144.6,141.0,127.5,123.8,122.7,121.1,118.7,116.6,115.2,107.6,88.5,78.5,75.4,71.1,70.7,70.5,70.4,70.0,69.5,67.0,55.6,50.1,49.5,47.8,46.6,46.3,42.0,41.7,39.7,39.6,39.4,38.6,36.8,35.5,34.2,33.5,33.1,32.8,30.7,28.0,27.7,26.6,26.0,23.7,23.6,23.5,18.3,17.2,16.8,15.4；HRMS(ESI):Calcd for[M+Na]⁺C₅₅H₈₃N₅NaO₁₂:1028.5936,found 1028.6029.

EXAMPLE 4 preparation of Compound M4

In this example, the same steps ① - ④ as in example 1 were used to obtain intermediate D4 starting from arabinose;

the same step (3) as in example 1 was employed, intermediate S1 and intermediate D4 reacted to give intermediate F4;

intermediate F4 using the same steps (4) to (6) as example 1 gave intermediate L4;

the same procedure (7) as in example 1 was followed, caffeic acid was reacted with propargylamine to give intermediate P1; (8) synthesis of Compound M4

P1(50mg, 0.19mmol) was weighed accurately and added to a 50M L round bottom flask, 2M L methanol was added to dissolve, thiophene-2-copper formate (3.6mg,0.019mmol) catalyst was added, intermediate L4 (149.9mg, 0.19mmol) was added, the reaction solution was stirred overnight at room temperature, T L C monitored for reaction, dichloromethane-methanol-water (50: 10: 1) was used as a developing agent, 365nm product was fluorescent and iodine developed, the reaction solution was filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and dichloromethane-methanol (6: 1) was eluted to give M4 as a white powder.

¹H-NMR(600MHz,pyridine-d₅):9.44(t,J＝5.5Hz,1H,N”-H),8.16(s,1H,Triazole-H),8.11(d,J＝15.6Hz,1H,H-7′’),7.55-7.54(m,2H,H-2′’,N-H),7.19-7.14(m,1H,H-5′’,6”),6.88(d,J＝15.5Hz,1H,H-8′’),5.46(t,J＝3.3Hz,1H,H-12),4.98(d,J＝5.6Hz,2H,H-10′’),4.78(d,J＝7.1Hz,1H,H-1’),4.55(t,J＝5.2Hz,2H,H-38),4.47-4.44(m,1H,H-2’),4.34-4.32(m,2H,H-5’),4.19-4.17(m,1H,H-3’),3.86-3.83(m,1H,H-4’),3.81(t,J＝5.2Hz,2H,H-37),3.77-3.55(m,12H,H-31～36),3.35(dd,J＝11.6,4.3Hz,1H,H-3),3.08(dd,J＝13.0,3.5Hz,1H,H-18),1.29(s,3H,CH₃),1.27(s,3H,CH₃),0.98(s,3H,CH₃),0.95(s,3H,CH₃),0.93(s,3H,CH₃),0.92(s,6H,2×CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.7,166.7,149.4,147.5,146.0,144.6,141.0,127.5,123.8,122.7,121.1,118.7,116.6,115.2,107.5,88.5,74.5,72.8,70.7,70.5,70.4,70.0,69.5,66.7,55.6,50.1,47.8,46.6,46.3,42.0,41.7,39.7,39.6,39.4,38.6,36.8,35.5,34.2,33.5,33.1,32.8,30.8,28.1,27.7,26.5,26.0,23.7,23.6,23.5,18.3,17.3,16.8,15.5；HRMS(ESI):Calcdfor[M+Na]⁺C₅₅H₈₃N₅NaO₁₂:1028.5936,found 1028.6014.

EXAMPLE 5 preparation of Compound N1

In this example, the same steps ① to ④ as in example 1 were carried out to obtain intermediate D1 using glucose as a starting material;

the same step (3) as in example 1 was employed, intermediate S1 and intermediate D1 reacted to give intermediate F1;

intermediate F1 using the same steps (4) to (6) as example 1 gave intermediate L1;

by the same step (7) as in example 1, 3-methoxy 4-hydroxycinnamic acid was reacted with propargylamine to give intermediate P2;

(8) synthesis of Compound N1

Accurately weighing P2(50mg, 0.19mmol), adding the P2 into a 50m L round-bottom flask, adding 2m L methanol for dissolution, adding a thiophene-2-copper formate (3.6mg,0.019mmol) catalyst, adding an intermediate L1 (155.6mg, 0.19mmol), stirring the mixture at room temperature for a night, monitoring the reaction at T L C, using a developing agent of dichloromethane-methanol-water (50: 10: 1), enabling a product to have fluorescence at 365nm and enable iodine to develop, filtering the reaction solution, concentrating the reaction solution under reduced pressure, purifying the residue through silica gel column chromatography, and eluting dichloromethane-methanol (6: 1) to obtain white powder N1.

¹H-NMR(600MHz,pyridine-d₅):9.42(t,J＝5.5Hz,1H,N”-H),8.19(s,1H,Triazole-H),8.07(d,J＝15.6Hz,1H,H-7′’),7.53(t,J＝5.2Hz,1H,N-H),7.22-7.15(m,3H,H-2′’,5′’,6”),6.90(d,J＝15.6Hz,1H,H-8′’),5.46(t,J＝3.3Hz,1H,H-12),5.01(d,J＝5.7Hz,2H,H-10′’),4.95(d,J＝7.8Hz,1H,H-1’),4.61-4.59(m,1H,H-2’),4.57(t,J＝5.1Hz,2H,H-38),4.43-4.41(m,1H,H-5’),4.29-4.22(m,2H,H-6’),4.07-4.01(m,2H,H-3’,4’),3.82(t,J＝5.1Hz,2H,H-37),3.77-3.55(m,15H,H-31～36,OCH₃),3.39(dd,J＝11.7,4.1Hz,1H,H-3),3.07(dd,J＝12.9,3.4Hz,1H,H-18),1.32(s,3H,CH₃),1.27(s,3H,CH₃),1.02(s,3H,CH₃),0.94(s,3H,CH₃),0.93(s,3H,CH₃),0.91(s,3H,CH₃),0.88(s,3H,CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.6,166.6,150.0,148.7,146.0,144.6,140.6,127.1,123.7,122.7,122.4,119.1,116.7,111.0,106.8,88.7,78.6,78.2,75.6,71.6,70.7,70.5,70.4,70.0,69.5,62.9,55.6,55.5,50.1,47.8,46.6,46.3,42.0,41.7,39.7,39.6,39.4,38.5,36.8,35.5,34.2,33.5,33.1,32.8,30.7,28.1,27.7,26.4,26.0,23.7,23.6,23.5,18.3,17.2,16.9,15.4；HRMS(ESI):Calcd for[M+Na]⁺C₅₇H₈₇N₅NaO₁₃:1072.6198,found1072.6287.

EXAMPLE 6 preparation of Compound N2

(8) synthesis of Compound N2

Accurately weighing P2(50mg, 0.19mmol), adding the P2 into a 50m L round-bottom flask, adding 2m L methanol for dissolution, adding a thiophene-2-copper formate (3.6mg,0.019mmol) catalyst, adding an intermediate L2 (152.6mg, 0.19mmol), stirring the mixture at room temperature for a night, monitoring the reaction at T L C, using dichloromethane-methanol-water (50: 10: 1) as a developing agent, enabling a product to have fluorescence at 365nm and iodine to be developed, filtering the reaction solution, concentrating the reaction solution under reduced pressure, purifying the residue through silica gel column chromatography, and eluting dichloromethane-methanol (6: 1) to obtain white powder N2.

¹H-NMR(600MHz,pyridine-d₅):9.43(t,J＝5.4Hz,1H,N”-H),8.19(s,1H,Triazole-H),8.06(d,J＝15.6Hz,1H,H-7′’),7.54(t,J＝5.1Hz,1H,N-H),7.21-7.14(m,3H,H-2′’,5′’,6”),6.90(d,J＝15.6Hz,1H,H-8′’),5.45(t,J＝3.3Hz,1H,H-12),5.00(d,J＝5.6Hz,2H,H-10′’),5.30(m,1H,H-1’),4.58-4.56(m,3H,H-2’,H-38),4.48-4.46(m,1H,H-5’),4.34-4.27(m,2H,H-3’,4’),3.82(t,J＝5.1Hz,2H,H-37),3.76-3.57(m,15H,H-31～36,OCH₃),3.14(dd,J＝11.6,4.2Hz,1H,H-3),3.06(dd,J＝13.2,3.5Hz,1H,H-18),1.65(d,J＝5.6Hz,3H,H-6’),1.24(s,3H,CH₃),0.93(s,3H,CH₃),0.92(s,3H,CH₃),0.91(s,6H,2×CH₃),0.89(s,3H,CH₃),0.80(s,3H,CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.7,166.6,150.0,148.7,145.9,144.6,140.6,127.0,123.7,122.6,122.3,119.0,116.6,111.0,104.2,88.3,73.9,72.7,72.3,70.6,70.4,70.4,70.0,69.7,69.5,55.5,55.3,50.1,47.7,46.6,46.3,41.9,41.7,39.7,39.5,39.0,38.3,36.7,35.4,34.2,33.5,33.0,32.7,30.7,28.1,27.7,26.0,25.6,23.6,23.6,23.5,18.3,17.2,16.6,15.3；HRMS(ESI):Calcd for[M+Na]⁺C₅₇H₈₇N₅NaO₁₂:1056.6249,found 1056.6329.

EXAMPLE 7 preparation of Compound N3

(8) synthesis of Compound N3

P2(50mg, 0.19mmol) was weighed accurately and added to a 50m L round bottom flask, 2m L methanol was added to dissolve, thiophene-2-copper formate (3.6mg,0.019mmol) catalyst was added, intermediate L3 (149.9mg, 0.19mmol) was added, the reaction solution was stirred overnight at room temperature, T L C monitored for reaction, dichloromethane-methanol-water (50: 10: 1) was used as a developing agent, 365nm product was fluorescent and iodine developed, the reaction solution was filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and dichloromethane-methanol (6: 1) was eluted to give N3 as a white powder.

¹H-NMR(600MHz,pyridine-d₅):9.42(t,J＝5.2Hz,1H,N”-H),8.19(s,1H,Triazole-H),8.07(d,J＝15.5Hz,1H,H-7′’),7.53(t,J＝5.2Hz,1H,N-H),7.23-7.15(m,3H,H-2′’,5′’,6”),6.90(d,J＝15.5Hz,1H,H-8′’),5.45(t,J＝3.3Hz,1H,H-12),5.01(d,J＝5.2Hz,2H,H-10′’),4.84(d,J＝7.4Hz,1H,H-1’),4.57(t,J＝4.5Hz,2H,H-38),4.41-4.38(m,1H,H-2’),4.24-4.16(m,2H,H-5’),4.04-4.02(m,1H,H-3’),3.84-3.79(m,3H,H-4’,H-37),3.77-3.56(m,15H,H-31～36,OCH₃),3.36(dd,J＝11.2,3.3Hz,1H,H-3),3.01(dd,J＝12.9,2.7Hz,1H,H-18),1.31(s,3H,CH₃),1.27(s,3H,CH₃),1.01(s,3H,CH₃),0.95(s,3H,CH₃),0.93(s,3H,CH₃),0.92(s,6H,2×CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.6,166.6,150.0,148.7,146.0,144.6,140.6,127.1,123.7,122.7,122.4,119.1,116.7,111.0,107.6,88.5,78.5,75.4,71.1,70.7,70.5,70.4,70.0,69.5,67.0,55.6,55.5,50.1,47.8,46.6,46.3,42.0,41.7,39.7,39.6,39.5,38.6,36.9,35.5,34.2,33.5,33.1,32.8,30.7,28.0,27.7,26.6,26.0,23.7,23.6,23.5,18.3,17.2,16.8,15.5；HRMS(ESI):Calcdfor[M+Na]⁺C₅₆H₈₅N₅NaO₁₂:1042.6092,found 1042.6179.

EXAMPLE 8 preparation of Compound N4

(8) synthesis of Compound N4

P2(50mg, 0.19mmol) was weighed accurately and added to a 50m L round bottom flask, 2m L methanol was added to dissolve, thiophene-2-copper formate (3.6mg,0.019mmol) catalyst was added, intermediate L4 (149.9mg, 0.19mmol) was added, the reaction solution was stirred overnight at room temperature, T L C monitored for reaction, dichloromethane-methanol-water (50: 10: 1) was used as a developing agent, 365nm product was fluorescent and iodine developed, the reaction solution was filtered, concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and dichloromethane-methanol (6: 1) was eluted to give N4 as a white powder.

¹H-NMR(600MHz,pyridine-d₅):9.41(t,J＝5.3Hz,1H,N”-H),8.19(s,1H,Triazole-H),8.06(d,J＝15.8Hz,1H,H-7′’),7.52(t,J＝5.1Hz,1H,N-H),7.22-7.14(m,3H,H-2′’,5′’,6”),6.90(d,J＝15.7Hz,1H,H-8′’),5.44(t,J＝3.3Hz,1H,H-12),5.01(d,J＝5.6Hz,2H,H-10′’),4.76(d,J＝7.1Hz,1H,H-1’),4.56(t,J＝5.1Hz,2H,H-38),4.44-4.42(m,1H,H-2’),4.32-4.31(m,2H,H-5’),4.17-4.15(m,1H,H-3’),3.84-3.81(m,3H,H-4’,H-37),3.75-3.56(m,15H,H-31～36,OCH₃),3.34(dd,J＝11.7,4.1Hz,1H,H-3),3.06(dd,J＝12.9,3.1Hz,1H,H-18),1.28(s,3H,CH₃),1.26(s,3H,CH₃),0.97(s,3H,CH₃),0.94(s,3H,CH₃),0.93(s,3H,CH₃),0.91(s,6H,2×CH₃)；¹³C-NMR(150MHz,pyridine-d₅):177.6,166.6,150.0,148.7,146.0,144.6,140.6,127.1,123.7,122.7,122.3,119.1,116.6,111.0,107.4,88.5,74.5,72.8,70.7,70.4,70.4,70.0,69.5,69.4,66.7,55.6,55.5,50.1,47.8,46.6,46.3,42.0,41.7,39.7,39.6,39.4,38.6,36.8,35.5,34.2,33.5,33.1,32.8,30.7,28.0,27.7,26.5,26.0,23.7,23.6,23.5,18.3,17.2,16.8,15.4；HRMS(ESI):Calcdfor[M+Na]⁺C₅₆H₈₅N₅NaO₁₂:1042.6092,found 1042.6171.

Test example 1 biological Activity test of araloside derivatives

8 araloside derivatives M1-M4 and N1-N4 are subjected to in vitro protection effect research on myocardial ischemia-reperfusion injury. Aralia chinensis monomer saponin (0.5 μ M) and 8 derivatives are prepared into three concentrations (0.02 μ M, 0.1 μ M and 0.5 μ M) respectively, added into H9c2 myocardial cells, pre-incubated for 12H, induced H9c2 myocardial cell injury by 6H of oxygen deficiency and 12H of reoxygenation, and cell viability is determined by MTT method. The results are shown in FIG. 1, the columns in the histogram of FIG. 1 depicting

Triplicate experiments, # p<0.01 was significantly different relative to the blank group; p<The difference between 0.01 and the model group was significant. P<A difference of 0.05 was significant with respect to the model group. The structural formula of aralia monomer saponin (prototype saponin) is as follows:

as can be seen from fig. 1d, at three concentrations of 0.02 μ M, 0.1 μ M, and 0.5 μ M, araloside derivative M4 has significant difference compared to the model group, and the cell survival rate is higher than that of the prototype saponin, so araloside derivative M4 has better activity than that of the prototype saponin (0.5 μ M) at three concentrations.

As can be seen from fig. 1h, at two concentrations of 0.1 μ M and 0.5 μ M, araloside derivative N4 has significant difference compared with the model group, and the cell survival rate is higher than that of the prototype saponin, so araloside derivative N4 is superior to the prototype saponin (0.5 μ M) at this concentration.

As can be seen from fig. 1b, at the concentration of 0.02 μ M, the araloside derivative M2 has significant difference compared to the model group, and the cell survival rate is higher than that of the prototype saponin, so the araloside derivative M2 is superior to that of the prototype saponin (0.5 μ M) at this concentration.

Therefore, the invention takes oleanolic acid and four kinds of sugar, caffeic acid or 3-methoxy 4-hydroxycinnamic acid as raw materials, retains the structural skeleton of oleanolic acid, aligns the hydroxyl group on the 3-position of the oleanolic acid to carry out glycosylation modification, modifies 28-position carboxyl, synthesizes the novel araloside derivative with the functions of treating cardiovascular and cerebrovascular diseases and the like, and has simple synthesis method and high product purity. Compared with Aralia elata monomer saponin, the Aralia elata saponin derivative provided by the invention has the following advantages: 1. the source is easy to obtain, and the synthesis is simple and convenient; 2. has better biological activity and solubility compared with the prototype; 3. the structure is brand new.

Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the idea of the invention, also technical features in the above embodiments or in different embodiments may be combined and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity. Therefore, any omissions, modifications, substitutions, improvements and the like that may be made without departing from the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims

1. An araloside derivative is characterized by having a structure shown in a general formula (I):

R₇is selected from H or CH₂OH；

R₈Is selected from H or CH₃；

R₉Selected from OH or OCH₃。

2. An araloside derivative according to claim 1, wherein R is₁And R₂In a different sense, R₃And R₄In a different sense, R₅And R₆Different.

3. The araloside derivative according to claim 2, wherein the araloside derivative is a compound represented by the following structural formula M1-M4 and N1-N4,

4. a process for the preparation of araloside derivatives according to any of claims 1 to 3, comprising the steps of:

the intermediate P1 reacts with the intermediates L1-L4 respectively to obtain araloside derivatives M1-M4;

the intermediate P2 reacts with the intermediates L1-L4 respectively to obtain araloside derivatives N1-N4;

the general formulas of D1-D4 are:

In intermediate D4, R₁＝H，R₂＝OBz，R₃＝OBz，R₄＝H，R₅＝OBz，R₆＝H，R₇＝H，R₈＝H；

5. The method for preparing an araloside derivative according to claim 4, wherein the intermediates D1-D4 are prepared by the following method:

the intermediates C1-C4 react with trichloroacetonitrile respectively to generate intermediates D1-D4,

the synthetic route of intermediate D1 is as follows:

the synthetic route of intermediate D2 is as follows:

the synthetic route of intermediate D3 is as follows:

the synthetic route of intermediate D4 is as follows:

6. the method for preparing araloside derivatives according to claim 4, wherein oleanolic acid is dissolved in methylene chloride, and tetrabutylammonium bromide and K are sequentially added₂CO₃Stirring the solution for 20-40 minutes, dropwise adding benzyl bromide at 0 ℃, and stirring for 1-3 days at room temperature to obtain an intermediate S1;

dissolving the intermediate P1 with methanol, adding a catalyst of thiophene-2-copper formate, then respectively adding the intermediates L1-L4, and stirring overnight at room temperature to obtain araloside derivatives M1-M4;

dissolving the intermediate P2 with methanol, adding a catalyst of thiophene-2-copper formate, then respectively adding the intermediates L1-L4, and stirring overnight at room temperature to obtain the araloside derivatives N1-N4.

7. The preparation method of the araloside monomer derivative according to claim 5, wherein the intermediates D1-D4 are prepared by the following method:

reacting the intermediates A1-A4 with 33% cyanogen bromide acetic acid solution at room temperature for 1-3 hours to obtain intermediates B1-B4;

8. The method of claim 5 or 7, wherein the monosaccharide is selected from glucose, rhamnose, xylose or arabinose.

9. A pharmaceutical composition comprising an araloside derivative according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

10. Use of an araloside derivative according to any one of claims 1 to 3 in the manufacture of a medicament for the protection of cardiovascular and cerebrovascular systems.