A method for synthesizing paeoniflorin derivatives

Abstract

The present invention provides a method for synthesizing a paeoniflorin derivative of formula III, which can significantly reduce the amount of reaction solvent used and shorten the reaction time, and has the characteristics of economic savings, simple operation, mild conditions, and greatly improved reaction yield. The method is suitable for carrying out a wider range of paeoniflorin structural modifications and can meet the needs of industrialization.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for synthesizing a paeoniflorin derivative. Background Art

[0002] As the main component of total glutoside of Paeony (TGP), paeoniflorin has been used in the clinical treatment of rheumatoid arthritis. However, TGP also has some shortcomings, such as slow onset, large individual differences in efficacy, and low bioavailability. Clinical use has also found that when the oral dose is increased, some patients will experience gastrointestinal reactions such as diarrhea and loss of appetite. Therefore, improving the efficacy and bioavailability of paeoniflorin by structural modification will be more conducive to patient recovery.

[0003] To this end, the prior art provides an esterification method using 4-dimethylaminopyridine (DMAP) as a catalyst. Although a paeoniflorin-6-O'-benzenesulfonate compound with better therapeutic effect is synthesized by this method, the method has the disadvantages of large amount of organic solvent, pyridine with certain reproductive toxicity, slow addition of acyl chloride as acylating agent, low yield, etc., which is not conducive to environmental protection and industrial production. Therefore, the development of an efficient and economical paeoniflorin esterification method will facilitate the search for paeoniflorin derivatives with better therapeutic effect and subsequent industrial production. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the above-mentioned prior art. To this end, the present invention provides a method for synthesizing paeoniflorin derivatives, which can significantly reduce the amount of reaction solvent, shorten the reaction time, and greatly improve the reaction yield and content.

[0005] Specifically, the present invention proposes a method for synthesizing a paeoniflorin derivative of formula III, and the reaction scheme is as follows:

[0006]

[0007] Specifically, the synthesis method comprises the following steps: after the paeoniflorin of formula I or the crude paeoniflorin is dissolved in an organic solvent, a metal catalyst is added for catalysis, and an esterification reaction is carried out under the action of an acid binding agent and an acyl chloride R-Cl to obtain a paeoniflorin derivative.

[0008] Wherein, the R-Cl is selected from C1~C 20 substituted and unsubstituted acyl chlorides and C1~C 20 Substituted and unsubstituted sulfonyl chlorides.

[0009] In some embodiments of the present invention, R is selected from:

[0010]

[0011] In some embodiments of the present invention, the crude paeoniflorin is derived from natural plant extracts, for example, it can be derived from at least one extract of white peony root, red peony root, moutan bark, dog head, peony root, and purple peony root, wherein the paeoniflorin content is greater than 40%.

[0012] In the present invention, a metal catalyst is used to catalyze the peony root glucoside The esterification reaction can significantly improve the reaction efficiency and product yield; the acyl chloride can be added all at once, and there is no need to add it by dropwise addition, so as to realize the paeoniflorin derivatives The synthesis provides a convenient industrial production scheme.

[0013] In some preferred embodiments of the present invention, the crude paeoniflorin is obtained by separating a natural plant extract by two-step column chromatography of alumina and silica gel, and the paeoniflorin content is greater than 40%; preferably, the paeoniflorin content in the natural plant extract is greater than 50%; more preferably, the paeoniflorin content in the natural plant extract is greater than 60%; most preferably, the paeoniflorin content in the natural plant extract is greater than 70%.

[0014] In some preferred embodiments of the present invention, based on paeoniflorin, the molar ratio of the paeoniflorin or the crude paeoniflorin to the acyl chloride is 1:(0.5-2); preferably 1:(0.8-2).

[0015] Compared with the existing synthesis process, in addition to reducing the amount of acyl chloride used due to the efficient and selective synthesis of the catalyst, the method of adding acyl chloride is also changed from slowly adding in drops over at least 3 hours in the existing technology to adding in one go, which is more conducive to industrial production.

[0016] In some more preferred embodiments of the present invention, the metal catalyst is selected from C1-C4 alkyl tin halides, aryl tin halides, C1-C4 alkyl tin oxides, C1-C4 alkyl tin sulfides or combinations thereof; further preferably, the metal catalyst is selected from dimethyl tin dichloride, diethyl tin dichloride, dibutyl tin dichloride, dimethyl tin sulfide, dimethyl tin oxide or combinations thereof.

[0017] In some more preferred embodiments of the present invention, the molar ratio of the paeoniflorin or the crude paeoniflorin to the metal catalyst is 1:(0.001-1.5), preferably 1:(0.01-0.2), and more preferably 1:(0.01-0.1).

[0018] In some more preferred embodiments of the present invention, the acid binding agent is selected from at least one of triethylamine, N,N'-diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate and sodium bicarbonate.

[0019] In some more preferred embodiments of the present invention, based on paeoniflorin, the molar ratio of the paeoniflorin or the crude paeoniflorin to the acid-binding agent is 1:(1-2); preferably 1:(1.2-1.6).

[0020] In some more preferred embodiments of the present invention, the mass volume ratio of the paeoniflorin or the crude paeoniflorin to the organic solvent is 1: (2-10) g / mL, preferably 1: (4-8) g / mL, and more preferably 1: (5-7) g / mL, based on paeoniflorin. Compared with the related art in which the amount of organic solvent used is 20-80 times the weight of paeoniflorin, the volume of the organic solvent in the present invention is only 2-10 times the weight of paeoniflorin, which significantly reduces the amount of organic solvent used in the reaction.

[0021] In some more preferred embodiments of the present invention, the organic solvent is at least one selected from tetrahydrofuran, acetone, methyl ethyl ketone, N,N'-dimethylformamide, acetonitrile, 1,4-dioxane, and dimethyl sulfoxide.

[0022] In some more preferred embodiments of the present invention, the temperature of the esterification reaction is -40°C to 70°C; more preferably 20°C to 30°C.

[0023] In some more preferred embodiments of the present invention, the esterification reaction time is 0.5 h to 10.0 h; preferably 1.0 h to 4.0 h.

[0024] In some more preferred embodiments of the present invention, after the esterification, a purification step is also included; further preferably, the purification is performed by extraction and concentration; even more preferably, the specific operation of the purification is: adding an extractant to the product of the esterification reaction for extraction, and concentrating the organic layer to obtain the paeoniflorin-6-O'-benzenesulfonate.

[0025] In some more preferred embodiments of the present invention, the extractant is ethyl acetate and water.

[0026] In some more preferred embodiments of the present invention, the mass volume ratio of the paeoniflorin or the crude paeoniflorin to the ethyl acetate is 1: (5-15) g / mL, preferably 1: (8-13) g / mL, calculated as paeoniflorin.

[0027] In some more preferred embodiments of the present invention, the mass volume ratio of the paeoniflorin or the crude paeoniflorin to the water is 1: (2.5-10) g / mL, preferably 1: (3-8) g / mL, and further preferably 1: (4-7) g / mL, calculated as paeoniflorin.

[0028] The beneficial effects of the present invention are:

[0029] The synthesis method of the present invention has the characteristics of small amount of catalyst and organic solvent, short reaction time, no need to add raw materials, etc., that is, it is economical, simple to operate, mild conditions, and can greatly improve the reaction yield, is suitable for more extensive structural modification of paeoniflorin, and can meet the needs of industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0031] Figure 1 It is the mass spectrum of the product of Example 1 of the present invention.

[0032] Figure 2 This is the hydrogen spectrum of the product of Example 1 of the present invention.

[0033] Figure 3 This is the carbon spectrum of the product of Example 1 of the present invention.

[0034] Figure 4 The liquid chromatograms of Example 1 and Comparative Example 1 of the present invention are shown.

[0035] Figure 5 It is the liquid chromatogram of comparative example 2 and comparative example 3 of the present invention. DETAILED DESCRIPTION

[0036] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0037] Example 1

[0038] In this example, paeoniflorin-6-O'-benzenesulfonate was prepared, and the specific process was as follows:

[0039] Under room temperature, 6g of pure paeoniflorin (content 98%) was dissolved in 25mL of acetone. After complete dissolution, 0.04g of dibutyltin dichloride was added for activation for 10min, and then 3.3mL of N,N'-diisopropylethylamine (DIPEA) and 1.6mL of benzenesulfonyl chloride were added in sequence for 2h reaction. TLC detection (developer ratio: chloroform: anhydrous ethanol = 8:1) was performed. After the reaction was complete, 60mL of ethyl acetate and 30mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 7.6g of white solid. The yield was 98.2% and the content was 93.1% according to the molar weight. The mass spectrum, hydrogen spectrum and carbon spectrum of the product are shown as follows: Figure 1 , Figure 2 , Figure 3 The liquid phase test results are shown in Figure 4 .

[0040] Example 2

[0041] This example prepares paeoniflorin-6-O'-p-toluenesulfonate, and the specific process is as follows:

[0042] Add dry ice to ethylene glycol to make a cooling bath at about -10°C, then dissolve 6 g of paeoniflorin (content 98%) in 25 mL of acetone and place in a cooling bath. After complete dissolution, add 0.06 g of dibutyltin dichloride to activate for 10 min, then add 3.3 mL of N, N'-diisopropylethylamine (DIPEA) and 2.4 g of p-toluenesulfonyl chloride in sequence to react for 3 h, and monitor the reaction by TLC. After the reaction is complete, extract with 70 mL of ethyl acetate and 35 mL of water, separate the liquids, and concentrate to dryness to obtain 7.6 g of a white solid. The yield calculated by molar weight is 95.8%, and the content is 90%.

[0043] Example 3

[0044] In this example, paeoniflorin-6-O'-2-fluorobenzenesulfonate was prepared, and the specific process was as follows:

[0045] At room temperature, 10 g of paeoniflorin (content 98%) was dissolved in 30 mL of N, N'-dimethylformamide (DMF). After complete dissolution, 0.10 g of dimethyltin dichloride was added for activation for 10 min, and then 4.3 g of potassium carbonate and 4.1 g of 2-fluorobenzenesulfonyl chloride were added in sequence for reaction for 3.5 h. The reaction was detected by TLC. After the reaction was complete, 100 mL of ethyl acetate and 70 mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 11.2 g of white solid with a yield of 84.1% and a content of 91%.

[0046] Example 4

[0047] This example prepares paeoniflorin-6-O'-4-chlorobenzenesulfonate, and the specific process is as follows:

[0048] At room temperature, 10 g of paeoniflorin (content 98%) was dissolved in 50 mL of acetonitrile. After complete dissolution, 0.10 g of dimethyltin dichloride was added for activation for 10 min, and then 3.5 mL of triethylamine and 4.1 g of 4-fluorobenzenesulfonyl chloride were added in sequence for reaction for 10 h. The reaction was detected by TLC. After the reaction was complete, 90 mL of ethyl acetate and 50 mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 11.8 g of white solid with a yield of 87.1% and a content of 91%.

[0049] Example 5

[0050] In this example, paeoniflorin-6-O'-3-methoxybenzenesulfonate was prepared, and the specific process was as follows:

[0051] At room temperature, 10 g of paeoniflorin (content 98%) was dissolved in 50 mL of tetrahydrofuran (THF). After complete dissolution, 4 g of dimethyltin dichloride was added for activation for 10 min, and then 3.5 mL of triethylamine and 2.95 ml of 3-methoxybenzenesulfonyl chloride were added in sequence for reaction for 0.5 h. The reaction was detected by TLC. After the reaction was complete, 90 mL of ethyl acetate and 50 mL of water were used for extraction and separation. The mixture was concentrated to dryness to obtain 13 g of a white solid with a yield of 96.3% and a content of 95.6%.

[0052] Example 6

[0053] This example prepares paeoniflorin-6-O'-4-iodobenzenesulfonate, and the specific process is as follows:

[0054] In a 40°C water bath, 10 g of paeoniflorin (98% content) was dissolved in 40 mL of acetone. After complete dissolution, 0.2 g of diethyltin dichloride was added for activation for 10 min, and then 3.5 mL of triethylamine and 9.4 g of 4-iodobenzenesulfonyl chloride were added in sequence to react for 5 h. The reaction was monitored by TLC. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 14.5 g of a white solid with a yield of 93.3% and a content of 90%.

[0055] Example 7

[0056] In this example, paeoniflorin-6-O'-3-phenylpropionate was prepared, and the specific process was as follows:

[0057] At 0°C, 6 g of paeoniflorin (content 98%) was dissolved in 30 mL of acetone. After complete dissolution, 0.07 g of dimethyltin sulfide was added for activation for 10 min, and then 3 mL of triethylamine and 1.9 mL of 3-phenylpropionyl chloride were added in sequence to react for 5 h. The reaction was detected by TLC. After the reaction was complete, 60 mL of ethyl acetate and 30 mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 12.6 g of white solid with a yield of 98.8% and a content of 93%.

[0058] Example 8

[0059] In this example, paeoniflorin-6-O'-benzenesulfonate was prepared, and the specific process was as follows:

[0060] In a 25°C water bath, 10 g of paeoniflorin (98% content) was dissolved in 40 mL of acetone. After complete dissolution, 0.07 g of dimethyltin oxide was added for activation for 10 min. Then 4.3 mL of triethylamine and 2.7 mL of benzenesulfonyl chloride were added in sequence for 5 h. The reaction was monitored by TLC. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were used for extraction and separation. The mixture was concentrated to dryness to obtain 11 g of a white solid with a yield of 85.1% and a content of 80%.

[0061] Example 9

[0062] In this example, paeoniflorin-6-O'-benzenesulfonate was prepared, and the specific process was as follows:

[0063] In a 65°C water bath, 10 g of paeoniflorin (98% content) was dissolved in 60 mL of acetonitrile. After complete dissolution, 0.08 g of dimethyltin oxide was added for activation for 10 min. Then 4.3 mL of triethylamine and 2.7 mL of benzenesulfonyl chloride were added in sequence for 10 h. The reaction was monitored by TLC. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were used for extraction and separation. The mixture was concentrated to dryness to obtain 11.7 g of a white solid with a yield of 90.6% and a content of 85%.

[0064] Example 10

[0065] In this example, paeoniflorin-6-O'-benzenesulfonate was prepared, and the specific process was as follows:

[0066] At room temperature, 10 g of paeoniflorin extract (content 44.7%) was dissolved in 60 mL of acetonitrile. After complete dissolution, 0.04 g of dimethyltin oxide was added for activation for 10 min. Then 2.3 mL of triethylamine and 1.7 mL of benzenesulfonyl chloride were added in sequence for reaction for 6 h. The reaction was detected by TLC. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were used for extraction and separation. The mixture was concentrated to dryness to obtain 4.4 g of white solid with a yield of 76.2% and a content of 36%.

[0067] Embodiment 11

[0068] In this example, paeoniflorin-6-O'-benzenesulfonate was prepared, and the specific process was as follows:

[0069] At room temperature, 10 g of crude paeoniflorin (content 66.3%) was dissolved in 60 mL of acetonitrile. After complete dissolution, 0.07 g of dimethyltin oxide was added for activation for 10 min, and then 4 mL of triethylamine and 2 mL of benzenesulfonyl chloride were added in sequence for reaction for 10 h. The reaction was detected by TLC. After the reaction was complete, 110 mL of ethyl acetate and 60 mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 6 g of white solid with a yield of 79.5% and a content of 57%.

[0070] Example 12

[0071] This example prepares crude paeoniflorin, and the specific process is as follows:

[0072] Take 50g of paeoniflorin extract (peoniflorin content 44.7%), add 100mL isopropanol to dissolve, then add 150g of neutral alumina to stir and adsorb, add the adsorbed neutral alumina to the chromatography column, use 200mL isopropanol to elute, collect the eluate, and concentrate to obtain 28.4g of paeoniflorin intermediate, with a paeoniflorin content of 78.3%. Use 100mL of solvent (chloroform: ethanol = 5: 1) to dissolve the obtained paeoniflorin intermediate, fill 450g of silica gel, the eluent is chloroform: ethanol = 9: 1, elute through silica gel column chromatography, elute 2.75L in total, collect the eluate, and concentrate under reduced pressure to obtain 23.7g of paeoniflorin crude product, with a content of 90.5%.

[0073] Embodiment 13

[0074] In this example, paeoniflorin-6-O'-benzenesulfonate was prepared, and the specific process was as follows:

[0075] At room temperature, 100 kg of crude paeoniflorin (content 90%) was stirred and dissolved completely in a reaction concentration tank with 312 kg of acetone, and then 1 kg of dimethyltin dichloride was added to the reaction tank for activation for 15 minutes, and then 27.6 kg of triethylamine and 36.7 kg of benzenesulfonyl chloride were added in sequence to react for 2 hours. During the reaction, the reaction was detected by TLC. After the reaction was complete, 1000 kg of ethyl acetate and 500 kg of water were added to the reaction concentration tank, stirred and extracted for 5 minutes, and then allowed to stand for 1 hour for separation. The organic layer was retained and concentrated to dryness and the solid content was measured at the same time: 300 mL of the organic layer solution was taken and concentrated to dryness to obtain 23.3 g, then the organic layer concentration was about 0.078 g / mL (0.078 kg / L), the volume after acetone and ethyl acetate conversion was 1506 L, then the organic layer had a total of about 117.5 kg of product, white solid, with a yield of 91.1% and a content of 82%.

[0076] Comparative Example 1

[0077] This comparative example prepared paeoniflorin-6-O'-benzenesulfonate according to the optimal conditions in the prior art, and the specific process is as follows:

[0078] At room temperature, 6 g of paeoniflorin (content 98%) was dissolved in a mixed solution of 36 mL of chloroform and 8 mL of pyridine, and then 50 mg of 4-dimethylaminopyridine was added to activate for 30 min. Within 3 h, 3.2 mL of benzenesulfonyl chloride was dissolved in 4 mL of dichloromethane and then dropped into the reaction solution for reaction. After the addition was complete, the reaction was continued for 6.5 h. The reaction was detected by TLC during the reaction. After the reaction was completed, the mixture was concentrated to an oily substance, and then 60 mL of ethyl acetate was added for extraction three times, with 60 mL of 1 M hydrochloric acid added each time. The organic layer was retained and concentrated to obtain 6.1 g of a yellow oily viscous substance with a yield of 78.8% and a content of 80.1%. The liquid phase detection results are shown in Figure 4 .

[0079] Comparative Example 2

[0080] This comparative example prepared paeoniflorin-6-O'-benzenesulfonate, and the specific process was as follows:

[0081] At room temperature, 6 g of crude paeoniflorin (content 90.5%) was dissolved in 25 mL of acetone. After complete dissolution, 0.04 g of dibutyltin dichloride was added for activation for 10 min, and then 3.3 mL of N, N'-diisopropylethylamine (DIPEA) and 1.6 mL of benzenesulfonyl chloride were added in sequence for 2 h. The reaction was detected by TLC. After the reaction was complete, 60 mL of ethyl acetate and 30 mL of water were used for extraction and separation, and the mixture was concentrated to dryness to obtain 7.5 g of white solid, with a yield of 91.1% and a content of 89.6%. The liquid phase detection results are shown in Figure 5 .

[0082] Comparative Example 3

[0083] This comparative example prepared paeoniflorin-6-O'-benzenesulfonate, and the specific process was as follows:

[0084] At room temperature, 6 g of crude paeoniflorin (content 90.5%) was dissolved in a mixed solution of 36 mL of chloroform and 8 mL of pyridine, and then 50 mg of 4-dimethylaminopyridine was added to activate for 30 min. Within 3 h, 3.2 mL of benzenesulfonyl chloride was dissolved in 4 mL of dichloromethane and then dropped into the reaction solution for reaction. After the addition was complete, the reaction was continued for 6.5 h. The reaction was detected by TLC during the reaction. After the reaction was completed, the mixture was concentrated to an oily substance, and then 60 mL of ethyl acetate was added for extraction three times, with 60 mL of 1 M hydrochloric acid added each time. The organic layer was retained and concentrated to obtain 5.4 g of a yellow oily viscous substance with a yield of 69.8% and a content of 73.9%. The liquid phase detection results are shown in Figure 5 .

[0085] Table 1 Summary of results of Example 1 and Comparative Examples

[0086]

[0087] Example 1 is compared with Comparative Examples 1 to 3, combined with Figure 4 and Figure 5 It can be seen that after pure paeoniflorin is reacted by different reaction methods, the content and yield of the technology of the present invention are better than those of the prior art: specifically, the content of pure paeoniflorin after the reaction of the technology of the present invention is 93.1% and the yield is 98.2%, of which there are 12 impurity peaks with an impurity content greater than 0.05% and 10 impurity peaks with an impurity content greater than 0.1%, while the content after the reaction using the prior art is 80.1% and the yield is 78.8%, of which there are 21 impurity peaks with an impurity content greater than 0.05% and 18 impurity peaks with an impurity content greater than 0.1%. In homemade paeoniflorin, the technology of the present invention is also better than the prior art; that is, the technology of the present invention has better tolerance to the reaction raw materials, and the reaction product has the characteristics of high content and less impurities, which is conducive to industrial production and reduces production costs.

[0088] In addition, in Examples 1 to 9, both the catalyst activation time and the addition time of intermediate materials such as acyl chloride and acid binding agent are significantly shorter than that of Comparative Example 1. The reaction solvent required for Comparative Example 1 is about twice that required for Example 1, and the second-class solvent pyridine with certain reproductive toxicity and high boiling point is also used in the reaction process of Comparative Example 1; in addition, in terms of the addition of acyl chloride, Examples 1 to 9 adopt a one-time addition method, while Comparative Example 1 adopts a slow dropwise addition method, which takes 3 hours, resulting in a longer reaction time. In addition, the present invention adopts an organic metal catalyst, which can significantly improve the reaction efficiency and shorten the reaction time; and in terms of reaction yield, Example 1 is more than 10% higher than Comparative Example 1. It can be seen that the technical solution of the present invention significantly reduces the amount of reaction solvent used, reduces production costs, and the production process is short in time, environmentally friendly, highly safe, and greatly improves the reaction yield.

[0089] The above is a detailed description of the embodiments of the present invention, but the present invention is not limited to the above embodiments. Various changes can be made within the knowledge of ordinary technicians in the relevant technical field without departing from the purpose of the present invention. In addition, the embodiments of the present invention and the features in the embodiments can be combined with each other without conflict.

Claims

1. A method for synthesizing a paeoniflorin derivative of formula III, characterized in that: The following steps are involved: After the paeoniflorin of formula I or the crude paeoniflorin is dissolved in an organic solvent, a metal catalyst is added to catalyze the esterification reaction under the action of an acid binding agent and an acyl chloride R-Cl to obtain a paeoniflorin derivative; Wherein, the crude peony root glycoside is derived from natural plant extracts, wherein the content of peony root glycoside is greater than 70%; The metal catalyst is selected from C1-C4 alkyl tin halide, C1-C4 alkyl tin oxide, C1-C4 alkyl tin sulfide or a combination thereof; Calculated on the basis of paeoniflorin, the mass volume ratio of the paeoniflorin or the crude paeoniflorin to the organic solvent is 1:(2-10) g / mL; The acid binding agent is selected from triethylamine, N,N'-diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or a combination thereof; The organic solvent is selected from tetrahydrofuran, acetone, methyl ethyl ketone, N,N'-dimethylformamide, acetonitrile, 1,4-dioxane, dimethyl sulfoxide or a combination thereof; The R is selected from 2. The method for synthesizing the paeoniflorin derivative according to claim 1, characterized in that: Calculated on the basis of paeoniflorin, the molar ratio of the paeoniflorin or the crude paeoniflorin to the acyl chloride is 1:(0.5-2).

3. The method for synthesizing the paeoniflorin derivative according to claim 1, characterized in that: The metal catalyst is selected from dimethyltin dichloride, diethyltin dichloride, dibutyltin dichloride, dimethyltin sulfide, dimethyltin oxide or a combination thereof.

4. The method for synthesizing the paeoniflorin derivative according to claim 1 or 3, characterized in that: Calculated on the basis of paeoniflorin, the molar ratio of the paeoniflorin or the crude paeoniflorin to the metal catalyst is 1:(0.001-1.5).

5. The method for synthesizing the paeoniflorin derivative according to claim 1, characterized in that: The molar ratio of the paeoniflorin or the crude paeoniflorin to the acid-binding agent is 1:(1-2).

6. The method for synthesizing the paeoniflorin derivative according to claim 2, characterized in that: Calculated on the basis of paeoniflorin, the molar ratio of the paeoniflorin or the crude paeoniflorin to the acyl chloride is 1:(0.8-2).

7. The method for synthesizing a paeoniflorin derivative according to claim 1 or 6, characterized in that: The mass volume ratio of the paeoniflorin to the organic solvent is 1: (4-8) g / mL.

8. The method for synthesizing a paeoniflorin derivative according to claim 1, characterized in that: The temperature of the esterification reaction is -40°C to 70°C.

9. The method for synthesizing a paeoniflorin derivative according to claim 1 or 8, characterized in that: The esterification reaction time is 0.5h to 10.0h.

10. The method for synthesizing the paeoniflorin derivative according to claim 1, characterized in that: After the esterification reaction, a purification step is also included.

Images