CN101712702B - Intermediate of flavonoid compound and preparation method and application thereof - Google Patents

Abstract

式D 式C 式AThe invention discloses a flavonoid compound intermediate as shown in formula C, and a preparation method thereof: in a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of a catalytic hydrogenation reaction catalyst, the flavonoid compound as shown in formula D The shown compound can be debenzyl by catalytic hydrogenation reaction; wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0~8; Bn is benzyl; Bz is benzoyl . The present invention also relates to the application of the flavonoid compound intermediate represented by formula C in the method for preparing the flavonoid compound represented by formula A. Compared with the existing methods for isolating and extracting flavonoids shown in Formula A from plants, the method for preparing flavonoids shown in Formula A from the flavonoid intermediates shown in Formula C of the present invention can be Large-scale industrial production is realized, and the method steps are simple, without strict requirements on special reagents and reaction conditions, and the yield and purity are high.

Type D Type C Type A

Description

A class of flavonoid compound intermediates and their preparation methods and applications

technical field

The invention relates to a class of flavonoid compound intermediates and a preparation method and application thereof.

Background technique

Common ischemic diseases include coronary heart disease, cerebral insufficiency, cerebral infarction and other heart and cerebrovascular ischemic diseases, which are one of the main diseases that endanger human health. Ischemic cerebrovascular diseases account for 50-70% of all cerebrovascular diseases, and are characterized by high morbidity, high mortality and high disability rate. health.

Apigenin 7-O-β-D-glucoside-4`-O-α-L-rhamnoside (Formula A) (English name: apigenin-7-O-β-D-glucopyranosyl-4`-O- α-L-rhamnopyranosid) is a flavonoid compound, which can be extracted and isolated from Ranunculus plants, such as Ranunculus sieboldii and R. sceleratus, and has certain anti-tumor, anti-HBV and The role of HSV-1. (Pan Yunxue, Study on the Chemical Constituents of Ranunculus chinensis, Chinese Journal of Traditional Chinese Medicine 2001, 8: 546-548).

Formula A

It has recently been found that the compound of formula A has a good effect on the prevention and treatment of ischemic diseases, and its effect on myocardial ischemia is studied by pituitary hormone-induced rat myocardial ischemia model, isoproterenol-induced rat myocardial ischemia model, and guinea pig three-dimensional heart model. It has been proved that it can significantly reduce heart rate, myocardial contractility and cardiac output. The activity of the compound of formula A was tested in the model of local cerebral ischemia induced by photochemical method, and it was found that the compound of formula A had a very significant effect on cerebral ischemic disease at a concentration of 2.5 mg to 5 mg/kg, and the effect was better than that of the positive control drug Nimodipine (. Xia Yuye et al., New application of apigenin 7-O-β-D-glucose-4'-O-α-L-rhamnoside, CN101053570A).

The compound of formula A has low content in plants, is difficult to separate and extract, and has low efficiency. Only 165 mg of compound of formula A can be extracted from a medicinal material with a dry weight of 17 kg (Li H, Zhou C, et al.Evaluation of antiviral activity of compound isolated from Ranunculus sieboldii and Ranunculus sceleratus. Plant Med 2005, 12: 1128-1133). However, in actual research and application, a large amount of pure product of formula A with reliable purity is required, and the compound of formula A isolated and extracted from plants alone cannot meet the demand.

Therefore, there is an urgent need to find a new synthetic method for the simple preparation of the compound of formula A.

Contents of the invention

The technical problem to be solved by the present invention is to provide a new intermediate compound for synthesizing the compound of formula A in order to overcome the existing complex and cumbersome operation of separating and extracting the compound of formula A from plants, the extraction efficiency is low, and it is difficult to meet the needs of research and application. and its preparation method, as well as its application in the preparation of formula A compound.

The flavonoid compound intermediate of the present invention is shown in formula C:

Formula C

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bz is benzoyl.

The present invention also relates to a preparation method of a flavonoid compound intermediate shown in formula C, which comprises the following steps: in a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of a catalytic hydrogenation reaction catalyst, the formula D The compound shown in formula C can be prepared by debenzylating the shown compound through catalytic hydrogenation reaction.

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bn is benzyl; Bz is benzoyl.

Wherein, the conditions of the catalytic hydrogenation reaction can be selected according to the conventional conditions of the catalytic hydrogenation reaction in the field of organic synthesis, and the preferred conditions are as follows: the catalyst for the catalytic hydrogenation reaction is preferably palladium carbon, palladium hydroxide, Raney One or more of nickel, rhodium, platinum and copper chromite, more preferably palladium carbon. The aprotic solvent is preferably dichloromethane and/or ethyl acetate; the alcohol solvent is preferably methanol and/or ethanol. The volume ratio of the aprotic solvent and the alcohol solvent is preferably 1:2-2:1, more preferably 1:1. The mixed solvent of the aprotic solvent and alcohol solvent is preferably a mixed solvent of dichloromethane and ethanol with a volume ratio of 1:1, or a mixed solvent of ethanol and ethyl acetate with a volume ratio of 1:1, More preferred is a mixed solvent of dichloromethane and ethanol with a volume ratio of 1:1. The amount of the solvent used may be 5 to 20 times, more preferably 10 times, the soluble amount of the reactant. The temperature of the catalytic hydrogenation reaction is preferably 30-50°C, more preferably 45°C. The pressure of the catalytic hydrogenation reaction is preferably a pressure level of 5-25 kg (hydrogenation tank), more preferably a pressure level of 15 kg (hydrogenation tank). The time for the catalytic hydrogenation reaction can be detected by TLC until the reactants are consumed, generally 8 to 12 hours.

In the present invention, the compound shown in formula D is preferably prepared by the following method: in an aprotic solvent, under the action of a condensation reagent, the compound shown in formula E and the compound shown in formula I 2,3,4-tribenzoyloxyrhamnose can be reacted to obtain the compound represented by formula D.

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bn is benzyl; Bz is benzoyl.

Above-mentioned reaction is Mitsunobu reaction, and each reaction condition can be selected by the routine condition of Mitsunobu reaction in the field of organic synthesis, and preferred condition is as follows: described condensing agent is preferably triphenylphosphine in combination with diethyl azodicarboxylate, Or triphenylphosphine combined with dibenzyl azodicarboxylate, more preferably triphenylphosphine combined with diethyl azodicarboxylate. The condensing agent is a combination of two compounds, and the molar ratio between the two compounds is preferably 1:1.5-1.5:1, more preferably 1:1. The molar ratio of the compound represented by formula E, 2,3,4-tribenzoyloxyrhamnose represented by formula I and the condensation reagent is preferably 1:1:1.2 to 1:2:4, more preferably The best is 1:1.2:1.8. The aprotic solvent is preferably dichloromethane and/or dimethylformamide, more preferably dimethylformamide. The amount of the solvent used may be 5 to 20 times, more preferably 10 times, the soluble amount of the reactant. The reaction temperature is preferably -30°C to 30°C, more preferably -20°C to 20°C. The reaction time can be detected by TLC until the reactants are consumed, generally 10-15 hours.

In the present invention, the 2,3,4-tribenzoyloxyrhamnose shown in formula I can refer to the literature (Chinese Academy of Sciences doctoral dissertation: the synthesis of some biologically active saponins and derivatives thereof and as biological The research of probe, Yang Zhiqi, 2004) public method makes, and synthetic route is as follows:

In the present invention, the compound shown in formula E is preferably prepared by the following method: in a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of an alkaline reagent, the compound shown in formula F The compound shown in formula E can be prepared by selectively dehydroxylating the protecting group.

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bn is benzyl.

Wherein, the various conditions of the reaction of the selective dehydroxylation protecting group can be selected from the conventional conditions of this type of reaction in the field of organic synthesis, and the preferred conditions are as follows: the preferred alkaline reagent is potassium carbonate, sodium carbonate and hydroxide One or more of potassium, more preferably potassium carbonate. The amount of the basic reagent used is preferably 0.1-0.3 times, more preferably 0.15 times, the molar amount of the compound represented by formula F. The aprotic solvent is dichloromethane and/or ethyl acetate; the alcohol solvent is methanol and/or ethanol. The volume ratio of the aprotic solvent and the alcohol solvent is preferably 1:2-2:1, more preferably 1:1. The mixed solvent of the aprotic solvent and alcohol solvent is preferably a mixed solvent of dichloromethane and ethanol with a volume ratio of 1:1, or a mixed solvent of dichloromethane and methanol with a volume ratio of 1:1, More preferably is a mixed solvent of dichloromethane and methanol with a volume ratio of 1:1. The amount of solvent used may be 5 to 20 times, more preferably 10 times, the soluble amount of the reactant. The temperature of the selective dehydroxylation reaction is preferably -10°C to 30°C, more preferably 0°C to 20°C. The reaction time for the selective deprotection can be detected by TLC until the reactants are consumed, generally 5-10 hours.

In the present invention, the compound shown as formula F can be obtained by referring to the method disclosed in the literature (Chinese patent: CN200810036839), and the synthetic route is:

(1) In an aprotic polar solvent, under the action of an organic base and a catalyst, the compound of formula G and the acid chloride or benzoyl chloride of the general formula CH ₃ (CH ₂ ) _n COCl are acylated to produce The compound shown in formula M is obtained.

(2) In an aprotic solvent, under the action of an inorganic base and a benzylation reaction catalyst, the compound shown in formula M is subjected to benzylation reaction with a benzylation reagent to obtain the compound shown in formula F. compound of.

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8; Bn is benzyl.

In step (1), the amount of acid chloride or benzoyl chloride with the general formula CH ₃ (CH ₂ ) _n COCl is preferably 4 to 6 times the molar amount of the compound shown in formula G. The organic base is preferably pyridine and/or triethylamine, more preferably triethylamine. The amount of the organic base is preferably 2-10 times the molar amount of the compound represented by formula G, more preferably 4-8 times. The catalyst for the acylation reaction can be a common catalyst for the acylation reaction in the field, such as pyridine or 4-dimethylaminopyridine, etc., preferably 4-dimethylaminopyridine. The amount of the catalyst for the acylation reaction is preferably 0.1 to 1 times the molar amount of the compound represented by formula G, more preferably 0.3 times. The aprotic polar solvent is preferably pyridine and/or dimethylformamide, more preferably dimethylformamide. The amount of the aprotic polar solvent used may be 1-10 times of the soluble amount of the compound represented by formula G, more preferably 3-5 times. The temperature of the acylation reaction is preferably 0-25°C. The time of the acylation reaction can be detected by TLC until the reactant is consumed, which is generally 8 hours. Among them, compounds represented by formula G are commercially available.

In step (2), the benzylation reagent may be a common benzylation reagent in the art, such as benzyl bromide or benzyl chloride, etc., preferably benzyl chloride. The amount of benzylation reagent used is preferably 5-20 times the molar amount of the compound represented by formula M, more preferably 6-8 times. The inorganic base is preferably one or more of potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide, preferably potassium carbonate. The amount of the inorganic base is preferably 5-15 times the molar amount of the compound represented by formula F, more preferably 9-10 times. The catalyst for benzylation reaction can be a common catalyst for benzylation reaction in the field, preferably potassium iodide or sodium iodide, more preferably potassium iodide. The amount of the benzylation reaction catalyst is preferably 0.1-1 times, more preferably 0.3-0.4 times the molar amount of the compound represented by formula M. The aprotic solvent is preferably one or more of dichloromethane, acetone, toluene and ethyl acetate, preferably acetone. The amount of the aprotic solvent used may be 1-10 times of the soluble amount of the compound represented by formula F, more preferably 5-7 times. The temperature of the benzylation reaction is preferably 40-60°C, more preferably 55°C. The time for the benzylation reaction can be detected by TLC until the reactants are consumed, generally 18-30 hours.

The present invention further relates to the application of flavonoids shown in formula C in the preparation of flavonoids shown in formula A, which includes the following steps:

(1) In a heterogeneous solution of an aprotic solvent and water, under the action of an alkaline reagent, under the action of a phase transfer catalyst, by the compound shown in formula C and 2,3 shown in formula H, 4,6-Tetrabenzoyloxyglucose bromide can be reacted to obtain the compound shown in formula B.

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bz is benzoyl.

Wherein, each condition of described reaction can be selected according to the routine condition of nucleophilic substitution reaction in the field of organic synthesis, and preferred condition is as follows: 2,3,4,6-tetrabenzoyloxy group shown in described formula H The molar ratio of bromoglucose to the compound represented by formula C is preferably 2:1-1:1, more preferably 1.5:1. The alkaline reagent is preferably one or more of potassium hydroxide, potassium carbonate and sodium carbonate, more preferably potassium carbonate. The amount of the basic reagent used is preferably 1.5 to 5 times the molar amount of the compound represented by formula C, more preferably 2 times. Described phase transfer catalyst is preferably one or more in tetrabutylammonium bromide, tetrabutylammonium iodide and methyl trioctyl ammonium chloride, more preferably tetrabutylammonium bromide . The amount of the phase transfer catalyst used is preferably 0.2-0.8 times, more preferably 0.5 times, the molar amount of the compound represented by formula C. The aprotic solvent is preferably dichloromethane and/or chloroform, more preferably dichloromethane. The volume ratio of the aprotic solvent and water is preferably 1:2-2:1, more preferably 1:1. The heterogeneous solution of the aprotic solvent and water is preferably a heterogeneous solution of dichloromethane and water with a volume ratio of 1:1, or a heterogeneous solution of chloroform and water with a volume ratio of 1:1 solution, more preferably a heterogeneous solution of dichloromethane and water with a volume ratio of 1:1. The amount of the solvent used may be 5 to 20 times, more preferably 10 times, the soluble amount of the reactant. The reaction temperature is preferably 30°C to 50°C, more preferably 40°C. The reaction time can be detected by TLC until the reactants are consumed, generally 15-30 hours.

Wherein, as shown in formula H, the available references of 2,3,4,6-tetrabenzoyloxy bromoglucose (Chinese Academy of Sciences doctoral dissertation: the synthesis of some biologically active saponins and derivatives thereof and as The research of biological probe, Yang Zhiqi, 2004) made by the disclosed method, and synthetic route is as follows:

(2) In a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of an alkaline reagent, the compound shown in formula B can be reacted with a dehydroxyl protecting group to obtain the flavonoids shown in formula A compound.

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bz is benzoyl.

Wherein, the conditions of the reaction of the dehydroxyl protecting group can be selected from the conventional conditions of this type of reaction in the field of organic synthesis, and the preferred conditions are as follows: the alkaline reagent is preferably potassium carbonate, potassium hydroxide and sodium methylate One or more, more preferably sodium methoxide. The amount of the basic reagent used is preferably 2 to 10 times the molar amount of the compound of formula B, more preferably 5 times. The aprotic solvent is preferably dichloromethane and/or ethyl acetate, more preferably dichloromethane. The alcohol solvent is preferably methanol and/or ethanol. The volume ratio of the aprotic solvent and the alcohol solvent is preferably 1:2-2:1, more preferably 1:1. The mixed solvent of described aprotic solvent and alcohol solvent is preferably the mixed solvent of dichloromethane and ethanol that the volume ratio is 1:1, or the mixed solvent of the dichloromethane and methanol that the volume ratio is 1:1, More preferred is a mixed solvent of dichloromethane and methanol with a volume ratio of 1:1. The amount of solvent used may be 5 to 20 times, more preferably 10 times, the soluble amount of the reactant. The temperature of the dehydroxylation protecting group reaction is preferably 10°C-30°C, more preferably 20°C. The reaction time of the dehydroxylation protecting group can be detected by TLC until the reactants are consumed, generally 2-5 hours.

In the above application, when n=4 is used, that is, when R ₁ is a compound of formula C of -CO(CH ₂ ) ₄ CH ₃ , compared with intermediates using other hydroxyl protecting groups, the compound has the best solubility, It has the best reaction efficiency, so it is used to prepare the compound of formula A, and the best overall yield can be obtained.

In the above-mentioned each step reaction of the present invention, the preferred conditions of each reaction condition can be combined arbitrarily, and each preferred example of the present invention can be obtained.

In summary, the best plan for preparing the flavonoids shown in formula A is as follows, and the reaction conditions of each step are the same as above:

(1) In a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of an alkaline reagent, the compound shown in Formula F undergoes a selective dehydroxylation protecting group reaction to prepare a compound shown in Formula E;

(2) In an aprotic solvent, under the action of a condensation reagent, the compound shown in formula E reacts with 2,3,4-tribenzoyloxyrhamnose shown in formula I to prepare Obtain the compound shown in formula D;

(3) In a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of a catalytic hydrogenation reaction catalyst, the compound shown in formula D is debenzylated through catalytic hydrogenation reaction to obtain the compound shown in formula C compound;

(4) In a heterogeneous solution of an aprotic solvent and water, under the action of an alkaline reagent, under the action of a phase transfer catalyst, by the compound shown in formula C and 2,3 shown in formula H, 4,6-tetrabenzoyloxyglucose bromide is reacted to obtain a compound shown in formula B;

(5) In a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of an alkaline reagent, the compound shown in formula B can be reacted with a dehydroxyl protecting group to obtain the flavonoids shown in formula A compound;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8, preferably n=4; Bn is benzyl; Bz is benzoyl. In the above optimal solution, when n=4, that is, when R ₁ is -CO(CH ₂ ) ₄ CH ₃ , each compound has the best solubility, so that the total yield of the compound of formula A is the highest.

The reagents and raw materials used in the present invention are commercially available unless otherwise specified.

The positive progress effect of the present invention is: the present invention provides a new flavonoid compound intermediate, which can be applied to the preparation of flavonoid compounds such as formula A, so as to realize large-scale industrial production, and the method has simple steps and no special Harsh requirements on reagents and reaction conditions, high yield and purity.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples.

Preparation of formula M compound:

Reference Example 1 Synthesis of 5,7,4'-O-trihexanoyl apigenin (compound of formula M, R ₁ is -CO(CH ₂ ) ₄ CH ₃ )

Apigenin (formula G, R ₁ is -CO(CH ₂ ) ₄ CH ₃ , 1.08g, 4mmol), 4-dimethylaminopyridine (155mg, 1.2mmol), triethylamine (2.6ml, 20mmol,) dissolved in In 10ml of dimethylformamide, add hexanoyl chloride (3.2ml, 22.8mmol) dropwise at 0°C, stir and react at 25°C for 8 hours (TLC detects that apigenin is consumed), the system is diluted with dichloromethane, and the organic phase is saturated with Wash with brine twice, dry over anhydrous sodium sulfate, filter and collect the organic phase, concentrate, and recrystallize the crude product from ethanol to obtain a white solid (1.95 g, yield 88%).

¹ H NMR (400MHz, CDCl3) δ: 0.91(m, 9H); 1.34(m, 12H); 1.75(m, 6H); 2.57(m, 4H); 2.76(d, 2H); ); 6.83(s, 1H); 7.26(d, 2H); 7.33(s, 1H); 7.88(d, 2H)

MS: 565(M+H); 1151(2M+Na)

Reference Example 2 Synthesis of 5,7,4'-O-triacetylpigenin (compound of formula M, R ₁ is -COCH ₃ )

According to the method of Reference Example 1, 5,7,4'-O-triacetyl apigenin can be obtained by replacing the raw material hexanoyl chloride with acetyl chloride.

Reference Example 3 Synthesis of 5,7,4'-O-tridecanoyl apigenin (compound of formula M, R ₁ is -CO(CH ₂ ) ₈ CH ₃ )

According to the method of Reference Example 1, the raw material hexanoyl chloride was replaced by decanoyl chloride to obtain 5,7,4'-O-tridecanoyl apigenin.

Reference Example 4 5,7,4'-O-tribenzoyl apigenin synthesis (formula M compound, R ₁ is benzoyl)

According to the method of Reference Example 1, the raw material hexanoyl chloride was replaced by benzoyl chloride to obtain 5,7,4'-O-tribenzoyl apigenin.

The preparation of formula F compound:

Reference Example 5 Synthesis of 5,4'-O-dihexanoyl-7-O-benzyl apigenin (compound of formula F, R is -CO(CH ₂ ) ₄ CH ₃ )

Formula M (R ₁ is -CO(CH ₂ ) ₄ CH ₃ , 4.4g, 7.8mmol), potassium carbonate (10g, 72mmol, 9eq), potassium iodide (390mg, 2.33mmol, 0.3eq) were dissolved in 50ml of acetone, Add benzyl chloride (6.7ml, 51mmol, 6.6 equivalents), react at 55°C for 24 hours (TLC detection formula M is consumed), cool, filter, and concentrate the reaction solution. The crude product is analyzed by n-hexane to obtain a white solid (3.9g, yield 90%).

¹ HNMR (400MHz, CDCl3) δ: 0.92(m, 6H); 1.43(m, 8H); 1.76(m, 4H); 2.56(m, 4H); 5.16(s, 2H); 6.55(s, 1H) ;6.68(d,1H);6.93(d,1H);7.24(d,2H);7.37(m,5H);7.83(d,2H)

MS: 579 (M+Na)

Reference Example 6 Synthesis of 5,4'-O-diacetyl-7-O-benzyl apigenin (compound of formula F, R is -COCH ₃ )

According to the method of Reference Example 5, the raw material formula M (R ₁ is -CO(CH ₂ ) ₄ CH ₃ ) is replaced by formula M (R ₁ is -COCH ₃ ), and 5,4′-O- Diacetyl-7-O-benzyl apigenin.

Reference Example 7 Synthesis of 5,4'-O-didecanoyl-7-O-benzyl apigenin (compound of formula F, R is -CO(CH ₂ ) ₈ CH ₃ )

According to the method of Reference Example 5, the raw material formula M (R ₁ is -CO(CH ₂ ) ₄ CH ₃ ) is replaced by the formula M (R ₁ is -CO(CH ₂ ) ₈ CH ₃ ), to obtain 5 , 4'-O-didecanoyl-7-O-benzyl apigenin.

Reference example 8 5, the synthesis of 4'-O-dihexanoyl-7-O-benzyl apigenin (compound of formula F, R is benzoyl)

According to the method of Reference Example 5, the raw material formula M (R ₁ is -CO(CH ₂ ) ₄ CH ₃ ) is replaced by formula M (R ₁ is benzoyl), and 5,4'-O- Dibenzoyl-7-O-benzyl apigenin.

The preparation of formula E compound:

Example 1 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 15ml of methanol, after cooling to 0°C, potassium carbonate (69mg, 0.5mmol) was added, and the temperature was naturally raised to 20°C, and reacted for 8 hours (TLC shows that formula F is consumed), add 1mol/L hydrochloric acid methanol to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone=30:1) to obtain a light yellow solid (1.52g, 90.3 %).

¹ H NMR (400MHz, CDCl ₃ ) δ: 0.92(m, 3H); 1.39(m, 4H); 1.46(m, 2H); 2.67(t, 2H); 5.31(s, 2H); 1H); 6.73(d, 1H); 7.06(d, 2H); 7.21(d, 1H); 7.36(m, 5H); 7.88(d, 2H), 9.02(s, 1H)

¹³ C NMR (CDCl ₃ ) δ: 13.9, 22.3, 24.1, 31.3, 34.3, 99.9, 105.9, 108.9, 111.0, 116.1, 116.2, 122.2, 127.4, 127.5, 127.8, 128.7, 128.8, 135.3, 150.3, 160.8 , 162.6, 162.7, 173.7, 177.0

MS-ESI: m/z 481 (M+Na)

Example 2 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 7.5ml of dichloromethane and 7.5ml of methanol, cooled to -10°C, added sodium carbonate (53mg, 0.5mmol), and naturally rose to 30°C, Reacted for 10 hours (TLC showed that Formula F was consumed), added 1 mol/L methanol hydrochloric acid to neutralize, removed the solvent by rotary evaporation, and purified by silica gel column chromatography (dichloromethane:acetone=30:1) to obtain a light yellow solid (1.40 g, 83.2%).

Example 3 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 30ml of methanol, after cooling to 0°C, potassium hydroxide (58.8mg, 1.05mmol) was added, and it was naturally raised to 30°C, and the reaction After 5 hours (TLC showed that Formula F was consumed), 1 mol/L of hydrochloric acid in methanol was added to neutralize, the solvent was removed by rotary evaporation, and silica gel column chromatography (dichloromethane: acetone = 30: 1) gave a light yellow solid (1.45g , 86.1%).

Example 4 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 15ml of ethanol, after cooling to -10°C, potassium carbonate (48.3mg, 0.35mmol) was added, and the temperature was naturally raised to 20°C, and the reaction After 10 hours (TLC showed that Formula F was consumed), 1 mol/L of hydrochloric acid methanol was added to neutralize, the solvent was removed by rotary evaporation, and silica gel column chromatography (dichloromethane: acetone = 30: 1) gave a light yellow solid (1.42g , 84.3%).

Example 5 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 7.5ml of ethanol, after cooling to 0°C, sodium carbonate (37mg, 0.35mmol) was added, and it was naturally raised to 30°C, and reaction 9 Hours (TLC showed that Formula F was consumed), adding 1 mol/L of hydrochloric acid methanol to neutralize, rotary evaporation to remove solvent, silica gel column chromatography separation and purification (dichloromethane: acetone = 30:1) to give a light yellow solid (1.38g, 82.0%).

Example 6 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 30ml of dichloromethane and 30ml of ethanol, after cooling to 0°C, potassium hydroxide (28mg, 0.5mmol) was added, and the temperature was naturally raised to 20°C, and reaction 8 Hours (TLC showed that Formula F was consumed), adding 1 mol/L of hydrochloric acid methanol to neutralize, rotary evaporation to remove the solvent, silica gel column chromatography separation and purification (dichloromethane: acetone = 30:1) to give a light yellow solid (1.46g, 86.7%).

Example 7 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 7.5ml of dichloromethane and 15ml of ethanol, after cooling to -10°C, potassium carbonate (48.3mg, 0.35mmol) was added, and it was naturally raised to 30°C, React for 10 hours (TLC shows that formula F is consumed), add 1mol/L hydrochloric acid methanol to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone = 30:1) to obtain a light yellow solid (1.44 g, 85.5%).

Example 8 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 30ml dichloromethane and 15ml methanol, cooled to -10°C and added sodium carbonate (37mg, 0.35mmol), and reacted for 10 hours at -10°C ( TLC shows that formula F is consumed), add 1mol/L hydrochloric acid methanol to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone=30:1) to obtain a light yellow solid (1.39g, 82.6% ).

Example 9 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 30ml dichloromethane and 30ml methanol, after cooling to 0°C, potassium hydroxide (19.6mg, 0.35mmol) was added, and reacted for 10 hours at 0°C ( TLC shows that formula F is consumed), add 1mol/L hydrochloric acid methanol to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone=30:1) to obtain a light yellow solid (1.41g, 83.8% ).

Example 10 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 7.5ml of methanol, after cooling to -10°C, potassium carbonate (69mg, 0.5mmol) was added, and it was naturally raised to 30°C, and the reaction After 10 hours (TLC showed that Formula F was consumed), 1 mol/L of hydrochloric acid methanol was added to neutralize, the solvent was removed by rotary evaporation, and silica gel column chromatography was separated and purified (dichloromethane: acetone = 30:1) to obtain a light yellow solid (1.46g , 86.7%).

Example 11 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula F (n=4, 2g, 3.5mmol) was dissolved in a mixed solvent of 30ml of dichloromethane and 15ml of ethanol, after cooling to 0°C, sodium carbonate (53mg, 0.5mmol) was added, naturally raised to 30°C, and reacted for 9 hours (TLC shows that formula F is consumed), add 1mol/L hydrochloric acid methanol to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone=30:1) to obtain a light yellow solid (1.39g, 82.6 %).

Example 12 Synthesis of 5-O-acetyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-COCH ₃ )

Formula F (n=0, 1.6g, 3.6mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 15ml of methanol, and after cooling to 0°C, potassium carbonate (69mg, 0.5mmol) was added, and it was naturally raised to 20°C, and reacted for 10 hours (TLC shows that formula F is consumed), add 1mol/L methanol hydrochloric acid to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone:=20:1) to obtain a light yellow solid (1.48g , 90.3%). MS-ESI: m/z 425 (M+Na)

Example 13 Synthesis of 5-O-decanoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R ₁ =-CO(CH ₂ ) ₈ CH ₃ )

Formula F (n=8, 2.4g, 3.6mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 15ml of methanol, after cooling to 0°C, potassium carbonate (69mg, 0.5mmol) was added, and the temperature was naturally raised to 20°C, and reaction 8 hours (TLC shows that formula F is consumed), add 1mol/L methanol hydrochloric acid to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone:=20:1) to obtain a light yellow solid (1.45g , 78.4%). MS-ESI: m/z537 (M+Na)

Example 14 Synthesis of 5-O-benzoyl-7-O-benzyl-4'-hydroxypigenin (compound of formula E, R = benzoyl)

Formula F (R ₁ =benzoyl, 2g, 3.5mmol) was dissolved in a mixed solvent of 15ml of dichloromethane and 15ml of methanol, after cooling to 0°C, potassium carbonate (69mg, 0.5mmol) was added, and the mixture was naturally raised to 20°C, React for 8 hours (TLC shows that formula F is consumed), add 1mol/L methanol hydrochloric acid to neutralize, remove the solvent by rotary evaporation, separate and purify by silica gel column chromatography (dichloromethane: acetone:=20:1) to obtain a light yellow solid ( 1.40 g, 86.2%). MS-ESI:m/z487(M+Na)

The preparation of formula D compound:

Example 15 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), Formula I (285.6mg, 0.6mmol) and triphenylphosphine (237mg, 0.9mmol), dissolved in 15mL of dimethylformamide, then cooled to -20°C , and diethyl azodicarboxylate (0.14 mL, 0.9 mmol) was added dropwise. Naturally raised to 20°C, reacted for 12 hours (TLC detected that formula I was consumed), removed the solvent under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain pale Yellow foam (209 mg, 45.6%).

¹ HNMR (400MHz, CDCl ₃ ) δ: 0.92(m, 3H), 1.2(s, 3H), 1.39(m, 4H), 1.83(m, 2H), 2.76(t, 2H), 4.29(s, 2H ), 5.18(s, 2H), 5.83(m, 2H), 6.05(dd, 1H), 6.57(d, 1H), 6.70(s, 1H), 6.70(s, 1H), 6.97(s, 1H) , 7.34 (m, 16H), 7.88 (m, 4H), 7.98 (d, 2H), 8.02 (d, 2H) ¹³ C NMR (CDCl ₃ ) δ: 13.9, 14.1, 17.7, 22.4, 24.1, 29.7, 31.4 , 34.4, 64.2, 67.9, 69.7, 70.5, 70.7, 71.5, 95.8, 99.9, 107.7, 108.9, 111.6, 116.6, 121.7, 125.7, 127.9, 128.3, 128.4, 128.7, 128.8, 129.2, 139.9, 139.7, 13 , 133.7, 133.8, 134.2, 135.5, 150.8, 158.5, 158.8, 161.8, 162.7, 165.6, 165.7, 172.3, 176.5

MS-ESI: m/z939(M+Na), 1856(2M+Na+H)

Example 16 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), Formula I (238mg, 0.5mmol) and triphenylphosphine (66mg, 0.3mmol), dissolved in 7.5mL dimethylformamide, then cooled to -30°C , and diethyl azodicarboxylate (0.04 mL, 0.3 mmol) was added dropwise. Naturally raised to 30°C, reacted for 15 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain light Yellow foam (180 mg, 39.3%).

Example 17 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), formula I (476mg, 1mmol) and triphenylphosphine (263.5mg, 1mmol) were dissolved in 15mL of dichloromethane, then cooled to -20°C, and the dichloromethane was added dropwise Diethyl nitrogen dicarboxylate (0.155 mL, 1 mmol). Naturally raised to 25°C, reacted for 10 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain pale Yellow foam (191 mg, 41.7%).

Example 18 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), Formula I (285.6mg, 0.6mmol) and triphenylphosphine (118.5mg, 0.45mmol), dissolved in 30mL of dimethylformamide, then cooled to -20 °C, dibenzyl azodicarboxylate (0.075 mL, 0.45 mmol) was added dropwise. Naturally raised to 20°C, reacted for 15 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain light Yellow foam (201 mg, 43.9%).

Example 19 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), formula I (238mg, 0.5mmol) and triphenylphosphine (237mg, 0.9mmol) were dissolved in 30mL of dichloromethane, then cooled to -30°C, and added dropwise Dibenzyl azodicarboxylate (0.10 mL, 0.6 mmol). Naturally raised to 30°C, reacted for 10 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain light Yellow foam (185 mg, 40.4%).

Example 20 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), formula I (476mg, 1mmol) and triphenylphosphine (527mg, 2mmol) were dissolved in 30mL of dimethylformamide, then cooled to -30°C, and added dropwise Dibenzyl azodicarboxylate (0.34 mL, 2 mmol). React at -30°C for 10 hours (TLC detects that formula I is consumed), remove the solvent under reduced pressure, and separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain a light yellow foam (180 mg, 39.3%).

Example 21 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), Formula I (285.6mg, 0.6mmol) and triphenylphosphine (237mg, 0.9mmol), dissolved in 15mL of dimethylformamide, then cooled to -20°C , and diethyl azodicarboxylate (0.21 mL, 1.35 mmol) was added dropwise. React at -20°C for 10 hours (TLC detects that Formula I is consumed), remove the solvent under reduced pressure, and separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain a light yellow foam (178 mg, 38.9%).

Example 22 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), formula I (476mg, 1mmol) and triphenylphosphine (351mg, 1.3mmol), were dissolved in 30mL of dimethylformamide, then cooled to 0°C, and added dropwise Dibenzyl azodicarboxylate (0.34 mL, 2 mmol). Reacted at 0°C for 15 hours (TLC detected that formula I was consumed), removed the solvent under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain a light yellow foam ( 165 mg, 36.0%).

Example 23 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), Formula I (238mg, 0.5mmol) and triphenylphosphine (237mg, 0.9mmol), dissolved in 7.5mL dimethylformamide, then cooled to -30°C , dibenzyl azodicarboxylate (0.23 mL, 1.35 mmol) was added dropwise. Naturally raised to 10°C, reacted for 15 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain light Yellow foam (172 mg, 37.6%).

Example 24 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240mg, 0.5mmol), Formula I (285.6mg, 0.6mmol) and triphenylphosphine (158mg, 0.6mmol), dissolved in 15mL of dimethylformamide, then cooled to -20°C , and diethyl azodicarboxylate (0.14 mL, 0.9 mmol) was added dropwise. Naturally raised to 30°C, reacted for 12 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain pale Yellow foam (155 mg, 33.8%).

Example 25 Synthesis of 5-O-hexanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula E (n=4, 240 mg, 0.5 mmol), formula I (476 mg, 1 mmol) and triphenylphosphine (237 mg, 0.9 mmol), were dissolved in 15 mL of dimethylformamide, then cooled to -30 ° C, drop Add dibenzyl azodicarboxylate (0.15 mL, 0.9 mmol). Naturally raised to 20°C, reacted for 15 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:2) to obtain light Yellow foam (150 mg, 32.8%).

Example 26 Synthesis of 5-O-acetyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-COCH ₃ )

Formula E (n=0, 200mg, 0.5mmol), Formula I (285.6mg, 0.6mmol) and triphenylphosphine (237mg, 0.9mmol), dissolved in 15mL of dimethylformamide, then cooled to -20°C , and diethyl azodicarboxylate (0.14 mL, 0.9 mmol) was added dropwise. Rise naturally to 20°C, react for 12 hours (TLC detects that formula I is consumed), remove the solvent under reduced pressure, and separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:1) to obtain light Yellow foam (160 mg, 37.9%). MS-ESI: m/z867(M+Na)

Example 27 Synthesis of 5-O-decanoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (formula Compound D, R ₁ =-CO(CH ₂ ) ₈ CH ₃ )

Formula E (n=8, 257mg, 0.5mmol), Formula I (285.6mg, 0.6mmol) and triphenylphosphine (237mg, 0.9mmol), dissolved in 15mL of dimethylformamide, then cooled to -20°C , and diethyl azodicarboxylate (0.14 mL, 0.9 mmol) was added dropwise. Naturally raised to 20°C, reacted for 12 hours (TLC detected that Formula I was consumed), removed the solvent under reduced pressure, and separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 10:1:3) to obtain pale Yellow foam (190 mg, 39.7%). MS-ESI: m/z979 (M+Na)

Example 28 Synthesis of 5-O-benzoyl-7-O-benzyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin ( Compound of formula D, R ₁ =benzoyl)

Formula E (R ₁ =benzoyl, 232 mg, 0.5 mmol), formula I (285.6 mg, 0.6 mmol) and triphenylphosphine (237 mg, 0.9 mmol), were dissolved in 15 mL of dimethylformamide, and then cooled to -20°C, diethyl azodicarboxylate (0.14 mL, 0.9 mmol) was added dropwise. Rise naturally to 20°C, react for 12 hours (TLC detects that formula I is consumed), remove the solvent under reduced pressure, and separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:1) to obtain light Yellow foam (195 mg, 42.6%). MS-ESI: m/z929 (M+Na)

Preparation of formula C compound:

Example 29 Synthesis of 5-O-hexanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula D (n=4, 200mg, 0.22mmol) was dissolved in a mixed solvent of 20mL of dichloromethane and 20mL of ethanol, 40mg of 5wt% palladium carbon was added, at 45°C, under the pressure of 15 kg level pressure grade (hydrogenation tank), add Pressurized catalytic hydrogenation for 10 hours, (TLC showed that formula D was consumed), filtered with diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:2), A white foam was obtained (143 mg, 78.7%)

¹ H NMR (400MHz, CDCl ₃ ) δ: 0.91(m, 3H), 1.15(s, 3H), 1.42(m, 4H), 1.85(m, 2H), 2.75(t, 2H), 4.27(m, 2H), 5.81(m, 2H), 6.05(dd, 1H), 6.57(d, 1H), 6.70(s, 1H), 6.97(s, 1H), 7.34(m, 15H), 7.98(d, 2H ), 8.02(d, 2H)

MS-ESI: m/z849 (M+Na)

Example 30 Synthesis of 5-O-hexanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula D (n=4, 200mg, 0.22mmol) was dissolved in a mixed solvent of 10mL of dichloromethane and 20mL of ethanol, and 15mg of Raney nickel was added, at 30°C, under the pressure of 25kg level pressure level (hydrogenation tank), pressurized Catalytic hydrogenation for 8 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:2) to obtain White foam (131mg, 72.1%)

Example 31 Synthesis of 5-O-hexanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula D (n=4, 200mg, 0.22mmol) was dissolved in a mixed solvent of 40mL dichloromethane and 40mL ethanol, 40mg of 5wt% palladium carbon was added, at 50°C, under the pressure of 25 kg grade (hydrogenation tank), add Pressurized catalytic hydrogenation for 12 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:2), A white foam was obtained (125 mg, 68.8%)

Example 32 Synthesis of 5-O-hexanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula D (n=4, 200mg, 0.22mmol) was dissolved in a mixed solvent of 10mL ethanol and 20mL ethyl acetate, 15mg of Raney nickel was added, at 30°C, pressurized under the pressure of 5kg level (hydrogenation tank) Catalytic hydrogenation for 8 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:2) to obtain White foam (129mg, 70.1%)

Example 33 Synthesis of 5-O-hexanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula D (n=4, 200mg, 0.22mmol) was dissolved in a mixed solvent of 20mL ethanol and 20mL ethyl acetate, added 5wt% palladium carbon 40m/g, 45°C, under the pressure of 15 kg level pressure level (hydrogenation tank) , pressurized catalytic hydrogenation for 10 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane=5:1:2 ), giving a white foam (139mg, 76.5%)

Example 34 Synthesis of 5-O-hexanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula D (n=4, 200mg, 0.22mmol) was dissolved in a mixed solvent of 40mL of dichloromethane and 40mL of ethanol, 15mg of Raney nickel was added, at 50°C, under the pressure of 20kg level pressure level (hydrogenation tank), pressurized Catalytic hydrogenation for 12 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:2), to obtain White foam (120mg, 66.0%)

Example 35 Synthesis of 5-O-acetyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ =-COCH ₃ )

Formula D (n=0, 189mg, 0.22mmol) was dissolved in a mixed solvent of 20mL dichloromethane and 20mL ethanol, 40mg of 5wt% palladium carbon was added, and at 45°C, under the pressure of 15 kg level pressure grade (hydrogenation tank), add Pressurized catalytic hydrogenation for 10 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 4:1:2), Obtained as white foam (119 mg, 70.8%) MS-ESI: m/z 793 (M+Na)

Example 36 Synthesis of 5-O-decanoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C, R ₁ ＝-CO(CH ₂ ) ₈ CH ₃ )

Formula D (n=8, 213mg, 0.22mmol) was dissolved in a mixed solvent of 20mL dichloromethane and 20mL ethanol, 40mg of 5wt% palladium carbon was added, and at 45°C, under the pressure of 15 kg grade (hydrogenation tank), add Pressurized catalytic hydrogenation for 10 hours, (TLC showed that formula D was consumed), filtered through diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 6:1:3), A white foam was obtained (133 mg, 69.1%)

MS-ESI: m/z905 (M+Na)

Example 37 Synthesis of 5-O-benzoyl-7-hydroxyl-4'-O-α-L-(2", 3", 4 "-tribenzoylrhamnose) apigenin (compound of formula C , R ₁ =-benzoyl)

Formula D (R ₁ =-benzoyl, 203mg, 0.22mmol) was dissolved in a mixed solvent of 20mL dichloromethane and 20mL ethanol, and 40mg of 5wt% palladium carbon was added, at 45°C, at a pressure level of 15kg (hydrogenation tank) Under pressure, pressurized catalytic hydrogenation for 10 hours, (TLC showed that formula D was consumed), filtered with diatomaceous earth, concentrated under reduced pressure, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1 : 1), a white foam was obtained (134 mg, 73.5%) MS-ESI: m/z 855 (M+Na)

Preparation of formula B compound:

Example 38 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane , then add 5mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (142mg, 67.4%).

¹ H-NMR (400MHz, CDCl ₃ ): δ8.15(m, 2H), 7.97(m, 8H), 7.87(m, 4H), 7.46(m, 25H), 7.03(d, 1H, J=1.7 Hz), 6.71(d, 1H, J=1.7Hz), 6.55(s, 1H), 6.04(m, 2H), 5.83(m, 5H), 5.64(d, 1H, J=7.2Hz), 4.78( d, 1H, J=9.3Hz), 4.53(m, 2H), 4.29(m, 1H), 2.67(m, 2H), 1.77(m, 2H), 1.38(m, 7H), 0.93(m, 3H )

¹³ C-NMR (100MHz, CDCl ₃ ): δ172.2, 166.1, 165.7, 165.6, 165.6, 165.6, 165.2, 165.0, 161.7, 160.0, 158.5, 133.7, 133.6, 133.6, 133.4, 133.3, 133.0, 130.0 ，129.9，129.9，129.9，129.8，129.8，129.7，129.7，129.6，129.6，129.6，129.3，129.3，129.3，129.1，129.1，129.1，129.0，129.0，129.0，128.7，128.7，128.7，128.6，128.6，128.6 , 128.6, 128.5, 128.5, 128.5, 128.4, 128.4, 128.4, 128.4, 128.3, 128.3, 128.3, 128.0, 128.0, 128.0, 128.0, 125.5, 116.8, 113.0, 109.4, 107.5, 90.7, 102.5 , 71.4, 71.4, 70.4, 69.6, 69.3, 67.9, 63.1, 34.1, 31.3, 24.0, 22.4, 17.7, 13.9,

ESI-MS (m/z): 1427[M+Na] ⁺

Example 39 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (99 mg, 0.15 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane , then add 5mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (116 mg, 55.2%).

Example 40 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (199 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane , then add 5mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, and separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (131mg, 62.4%).

Example 41 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (199.5 mg, 0.3 mmol), sodium carbonate (32 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane Then add 5mL of water, stir at 40°C for 24 hours, (TLC shows that the formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous Dry over sodium sulfate, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (130mg, 62.1%).

Example 42 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (118 mg, 0.18 mmol), potassium hydroxide (17 mg, 0.3 mmol) and tetrabutylammonium iodide (32 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane Then add 5mL of water, stir at 40°C for 15 hours, (TLC shows that the formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous Dry over sodium sulfate, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (132mg, 63.0%).

Example 43 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane , then add 10mL of water, stir at 40°C for 30 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (120mg, 57.4%).

Example 44 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120mg, 0.15mmol), formula H (151mg, 0.23mmol), potassium carbonate (41mg, 0.3mmol) and tetrabutylammonium bromide (24mg, 0.075mmol) were dissolved in 10mL chloroform, then Add 5mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution in turn, and the organic phase is dried with anhydrous sodium sulfate , filtered and collected the organic phase, concentrated, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a pale yellow foam (135 mg, 64.3%).

Example 45 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120mg, 0.15mmol), formula H (151mg, 0.23mmol), potassium carbonate (30mg, 0.225mmol) and tetrabutylammonium iodide (32mg, 0.075mmol) were dissolved in 10mL chloroform, then Add 10mL of water, stir at 50°C for 30 hours, (TLC shows that the formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is dried with anhydrous sodium sulfate , filtered and collected the organic phase, concentrated, separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (115 mg, 54.7%).

Example 46 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (100 mg, 0.75 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 2 mL of dichloromethane , then add 2mL of water, stir at 30°C for 15 hours, (TLC shows that the formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (131mg, 62.3%).

Example 47 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120mg, 0.15mmol), formula H (151mg, 0.23mmol), potassium carbonate (41mg, 0.3mmol) and methyltrioctylammonium chloride (30mg, 0.075mmol) were dissolved in 10mL of dichloro in methane, then add 20mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with Dry over sodium sulfate, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (140 mg, 66.8%).

Example 48 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (10 mg, 0.03 mmol) were dissolved in 5 mL of dichloromethane , then add 5mL of water, stir at 40°C for 30 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (125mg, 59.5%).

Example 49 5-O-hexanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₄ CH ₃ )

Formula C (n=4, 120 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (38 mg, 0.12 mmol) were dissolved in 10 mL of dichloromethane , then add 10mL of water, stir at 45°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (128mg, 61.4%).

Example 50 5-O-acetyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3 ", 4 "-tribenzoylrhamnose) apigenin synthesis (compound of formula B, R ₁ =-CO CH ₃ )

Formula C (n=0, 115 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane , then add 5mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 5:1:3) to obtain a light yellow foam (116mg, 57.4%). ESI-MS(m/z): 1371[M+Na] ⁺

Example 51 5-O-decanoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2" , 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =-CO(CH ₂ ) ₈ CH ₃ )

Formula C (n=8, 132 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL of dichloromethane , then add 5mL of water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with anhydrous sulfuric acid Dry over sodium, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 9:1:3) to obtain a light yellow foam (131mg, 60.1%). ESI-MS (m/z): 1483[M+Na] ⁺

Example 52 5-O-benzoyl-7-O-β-D-(2", 3", 4", 6"-tetrabenzoylglucose)-4'-O-α-L-(2 ", 3", 4"-tribenzoylrhamnose) apigenin (compound of formula B, R ₁ =benzoyl)

Formula C (R ₁ =benzoyl, 125 mg, 0.15 mmol), formula H (151 mg, 0.23 mmol), potassium carbonate (41 mg, 0.3 mmol) and tetrabutylammonium bromide (24 mg, 0.075 mmol) were dissolved in 5 mL di Chloromethane, then add 5mL water, stir at 40°C for 24 hours, (TLC shows that formula H is consumed), the reaction solution is diluted with dichloromethane, washed with 1mol/L HCl solution, water and saturated saline solution successively, and the organic phase is washed with Dry over anhydrous sodium sulfate, filter and collect the organic phase, concentrate, separate and purify by silica gel column chromatography (petroleum ether: ethyl acetate: dichloromethane = 7:1:1) to obtain a light yellow foam (111mg, 52.5%). ESI-MS (m/z): 1433[M+Na] ⁺

The preparation of formula A compound:

Example 53 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50mg, 0.036mmol) in 3mL of dichloromethane, then add 3mL of methanol, add sodium methoxide (10mg, 0.18mmol), and react at 20°C for 3 hours, (TLC detects that Formula B is consumed) Add 2 mol/L hydrochloric acid/methanol solution for neutralization, remove the solvent under reduced pressure and concentrate, then perform silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (19 mg, 88%).

¹ H-NMR (400MHz, C ₆ D ₆ N): δ8.07(d, 2H, J=8.8Hz), 7.45(d, 2H, J=8.8Hz), 7.23(d, 1H, J=1.62Hz ), 7.07(s, 1H), 6.96(d, 1H, J=2Hz), 6.22(s, 1H), 5.92(d, 1H, J=7.7Hz), 4.74(m, 2H), 4.36(m, 8H), 1.67(d, 3H, J=6.2Hz)

¹³ C-NMR (100MHz, C ₆ D ₆ N): δ183.2, 164.8, 164.5, 160.5, 158.3, 159.6, 129.1, 129.1, 125.1, 117.7, 117.7, 106.9, 105.3, 102.0, 101.2, 100.0, 96.0, 79.3, 78.4, 74.9, 73.8, 73.7, 72.5, 71.8, 71.5, 62.6, 18.9

ESI-MS(m/z): 601[M+Na] ⁺ , 613[M+Cl] ^- , HR-MS: m/z calcd for C ₂₇ H ₃₁ O ₁₄ ⁺¹

Example 54 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50 mg, 0.036 mmol) in 3 mL of ethyl acetate, then add 3 mL of methanol, add sodium methoxide (10 mg, 0.18 mmol), and react at 20°C for 3 hours, (TLC detects that Formula B is consumed ) was neutralized by adding 2mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (17mg, 80%).

Example 55 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50mg, 0.036mmol) in 6mL of dichloromethane, then add 3mL of methanol, add sodium methoxide (10mg, 0.18mmol), and react at 20°C for 3 hours, (TLC detects that Formula B is consumed) Add 2 mol/L hydrochloric acid/methanol solution for neutralization, remove the solvent under reduced pressure and concentrate, then perform silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (17 mg, 80%).

Example 56 Synthesis of Apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50mg, 0.036mmol) in 3mL of dichloromethane, then add 3mL of ethanol, add sodium methoxide (10mg, 0.18mmol), and react at 30°C for 5 hours, (TLC detects that Formula B is consumed ) was neutralized by adding 2mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (17mg, 80%).

Example 57 Synthesis of Apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50mg, 0.036mmol) in 3mL of dichloromethane, then add 6mL of methanol, add sodium methoxide (10mg, 0.18mmol), and react at 20°C for 3 hours, (TLC detects that Formula B is consumed) Add 2 mol/L hydrochloric acid/methanol solution for neutralization, remove the solvent under reduced pressure and concentrate, then perform silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (18 mg, 84%).

Example 58 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Formula B (n=4, 50mg, 0.036mmol) was dissolved in 6mL of dichloromethane, then 6mL of methanol was added, potassium hydroxide (10mg, 0.18mmol) was added, and after reacting at 20°C for 3 hours, (TLC detected the consumption of formula B Complete) Add 2mol/L hydrochloric acid/methanol solution for neutralization, remove the solvent under reduced pressure and concentrate, then perform silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (16mg, 75%).

Example 59 Synthesis of Apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50mg, 0.036mmol) in 3mL of dichloromethane, then add 3mL of methanol, add sodium methoxide (25mg, 0.18mmol), and react at 30°C for 5 hours, (TLC detects that Formula B is consumed ) was neutralized by adding 2 mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (19 mg, 88%).

Embodiment 60 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve formula B (n=4, 50mg, 0.036mmol) in 1.5mL of dichloromethane, then add 1.5mL of methanol, add sodium methoxide (10mg, 0.18mmol), and react at 20°C for 3 hours, (TLC detects formula B Consumption) was neutralized by adding 2 mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (18 mg, 85%).

Example 61 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve formula B (n=4, 50 mg, 0.036 mmol) in 3 mL of dichloromethane, then add 3 mL of methanol, add sodium methoxide (20 mg, 0.36 mmol), and react at 10°C for 2 hours, (TLC detects that formula B is consumed ) was neutralized by adding 2 mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (19 mg, 88%).

Example 62 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=4, 50mg, 0.036mmol) in 3mL of dichloromethane, then add 3mL of methanol, add sodium methoxide (4mg, 0.07mmol), and react at 30°C for 5 hours, (TLC detects that Formula B is consumed ) was neutralized by adding 2mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (17mg, 80%).

Example 63 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=0, 48mg, 0.036mmol) in 3mL of dichloromethane, then add 3mL of methanol, add sodium methoxide (10mg, 0.18mmol), and react at 20°C for 3 hours, (TLC detects that Formula B is consumed) Add 2 mol/L hydrochloric acid/methanol solution for neutralization, remove the solvent under reduced pressure and concentrate, then perform silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (18 mg, 84%).

Example 64 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve Formula B (n=8, 53mg, 0.036mmol) in 3mL of dichloromethane, then add 3mL of methanol, add sodium methoxide (10mg, 0.18mmol), and react at 20°C for 3 hours, (TLC detects that Formula B is consumed) Add 2 mol/L hydrochloric acid/methanol solution for neutralization, remove the solvent under reduced pressure and concentrate, then perform silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (16 mg, 75%).

Example 65 Synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

Dissolve formula B (R ₁ =benzoyl, 51 mg, 0.036 mmol) in 3 mL of dichloromethane, then add 3 mL of methanol, add sodium methoxide (10 mg, 0.18 mmol), and react at 20°C for 3 hours, (TLC detects formula B Consumption) was neutralized by adding 2 mol/L hydrochloric acid/methanol solution, the solvent was removed under reduced pressure and concentrated, followed by silica gel column chromatography (dichloromethane:methanol=4:1) to obtain a yellow solid (19 mg, 88%).

Embodiment 66～69 the synthesis of apigenin-7-O-β-D-glucoside-4'-O-α-L-rhamnoside (compound of formula A)

In Examples 66-69, the reaction conditions of each step are the same. From the comparison of the data in the above table, it can be seen that when R ₁ is -CO(CH ₂ ) ₄ CH ₃ , compared with intermediates using other hydroxyl protecting groups, Both step yield and total yield are higher.

Claims (17)

1. The flavonoid compound intermediate shown in formula C;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0-8; Bz is benzoyl. 2. The flavonoid compound intermediate shown in formula C as claimed in claim 1, characterized in that: said n=4. 3. the preparation method of the flavonoid compound intermediate shown in formula C as claimed in claim 1, is characterized in that it comprises the steps: in the mixed solvent of aprotic solvent and alcoholic solvent, in catalytic hydrogenation reaction catalyst Under the action of the compound shown in formula D, the compound shown in formula C can be obtained by debenzylating the compound shown in formula D through catalytic hydrogenation reaction;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0～8; Bn is benzyl; Bz is benzoyl; the aprotic solvent is dichloromethane and/or Ethyl acetate; the alcohol solvent is methanol and/or ethanol; the catalytic hydrogenation catalyst is palladium carbon and/or Raney nickel. 4. preparation method as claimed in claim 3 is characterized in that: the volume ratio of described aprotic solvent and alcoholic solvent is 1: 2～2: 1; The temperature of described catalytic hydrogenation reaction is 30～50 °C; the pressure of the catalytic hydrogenation reaction is 5-25 kg. 5. preparation method as claimed in claim 3 is characterized in that: the mixed solvent of described aprotic solvent and alcoholic solvent is the mixed solvent of methylene chloride and ethanol that volume ratio is 1: 1, or volume ratio is 1:1 mixed solvent of ethanol and ethyl acetate. 6. The preparation method according to claim 3, characterized in that: the compound shown in formula D is prepared by the following method: in an aprotic solvent, under the action of a condensation reagent, as shown in formula E The compound shown in formula I is reacted with 2,3,4-tribenzoyloxyrhamnose shown in formula I, and the compound shown in formula D can be prepared;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0～8; Bn is benzyl; Bz is benzoyl; the aprotic solvent is dichloromethane and/or Dimethylformamide; the condensation reagent is triphenylphosphine combined with diethyl azodicarboxylate, or triphenylphosphine combined with azodicarboxylate dibenzyl. 7. The preparation method according to claim 6, characterized in that: the condensing agent is triphenylphosphine and diethyl azodicarboxylate in a molar ratio of 1:1.5 to 1.5:1, or the molar ratio 1:1.5～1.5:1 triphenylphosphine and dibenzyl azodicarboxylate, such as the compound shown in formula E, the 2,3,4-tribenzoyloxyrhamna shown in formula I The molar ratio of sugar and condensation reagent is 1:1:1.2 to 1:2:4; the reaction temperature is -30°C to 30°C. 8. The preparation method according to claim 6, characterized in that: the compound shown in formula E is prepared by the following method: in a mixed solvent of an aprotic solvent and an alcoholic solvent, in an alkaline reagent Under the action, the compound shown in formula E can be prepared as the compound shown in formula E through selective dehydroxylation reaction of the compound shown in formula F;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0～8; Bn is benzyl; the aprotic solvent is dichloromethane and/or ethyl acetate; The alcohol solvent is methanol and/or ethanol; the alkaline reagent is one or more of potassium carbonate, sodium carbonate and potassium hydroxide. 9. preparation method as claimed in claim 8 is characterized in that: the consumption of described alkaline reagent is 0.1～0.3 times of the compound molar weight shown in formula F; The described aprotic solvent and alcoholic solvent The volume ratio is 1:2-2:1; the temperature of the selective dehydroxylation protecting group reaction is -10°C-30°C. 10. preparation method as claimed in claim 8 is characterized in that: the mixed solvent of described aprotic solvent and alcoholic solvent is the mixed solvent of methylene chloride and ethanol that volume ratio is 1: 1, or volume ratio is 1:1 mixed solvent of dichloromethane and methanol. 11. The preparation method according to any one of claims 3, 6 and 8, characterized in that: the time for the reaction is to detect that the reactants are consumed. 12. The preparation method according to any one of claims 3, 6 and 8, characterized in that: said n=4. 13. The application of the flavonoid compound intermediate shown in formula C as claimed in claim 1 in the preparation of flavonoid compound shown in formula A, is characterized in that it comprises the steps: (1) In a heterogeneous solution of an aprotic solvent and water, under the action of an alkaline reagent, under the action of a phase transfer catalyst, by the compound shown in formula C and 2,3 shown in formula H, 4,6-tetrabenzoyloxyglucose bromide reacts to obtain the compound shown in formula B;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0~8; Bz is benzoyl; the aprotic solvent is dichloromethane and/or chloroform; the The alkaline reagent is one or more of potassium hydroxide, potassium carbonate and sodium carbonate; the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylammonium iodide and methyl trioctyl ammonium chloride one or more of (2) In a mixed solvent of an aprotic solvent and an alcohol solvent, under the action of an alkaline reagent, the compound shown in formula B can be reacted with a dehydroxyl protecting group to obtain the flavonoids shown in formula A compound;

Wherein, R ₁ is -CO(CH ₂ ) _n CH ₃ or benzoyl; n=0~8; Bz is benzoyl; the aprotic solvent is dichloromethane and/or ethyl acetate; The alcohol solvent methanol and/or ethanol; the alkaline reagent is potassium hydroxide and/or sodium methylate. 14. The application according to claim 13, characterized in that: In step (1), the molar ratio of the 2,3,4,6-tetrabenzoyloxyglucose bromide represented by the formula H to the compound represented by the formula C is 2:1 to 1:1; The amount of the basic reagent is 1.5 to 5 times the molar amount of the compound shown in formula C; the amount of the phase transfer catalyst is 0.2 to 0.8 times the molar amount of the compound shown in formula C; the non- The volume ratio of the protic solvent and water is 1:2 to 2:1; the temperature of the reaction is 30°C to 50°C; In step (2), the amount of the basic reagent is 2 to 10 times the molar weight of the compound of formula B; the volume ratio of the aprotic solvent to the alcohol solvent is 1:2 to 2:1; the The temperature of the dehydroxylation protecting group reaction is 10°C to 30°C. 15. The application according to claim 13, characterized in that: In step (1), the heterogeneous solution of the aprotic solvent and water is a heterogeneous solution of dichloromethane and water with a volume ratio of 1:1, or a mixture of chloroform and water with a volume ratio of 1:1. heterogeneous solution; In step (2), the mixed solvent of the aprotic solvent and alcohol solvent is a mixed solvent of dichloromethane and ethanol with a volume ratio of 1:1, or a mixed solvent of dichloromethane and methanol with a volume ratio of 1:1. Mixed solvents. 16. The application according to claim 13, characterized in that: the time for the reaction is to detect that the reactant is consumed. 17. The application according to claim 13, characterized in that: said n=4.