CN115677790A

CN115677790A - Method for synthesizing paeoniflorin derivative

Info

Publication number: CN115677790A
Application number: CN202110839768.8A
Authority: CN
Inventors: 唐顺之; 许文东; 袁诚; 傅玉萍; 彭万才; 白柏; 李松涛; 李继荣; 魏劭恒; 陈文�; 李佳俐; 李遥; 毛禹康
Original assignee: Guangzhou Hanfang Pharmaceutical Co ltd
Current assignee: Guangzhou Hanfang Pharmaceutical Co ltd
Priority date: 2021-07-23
Filing date: 2021-07-23
Publication date: 2023-02-03
Also published as: WO2023000518A1

Abstract

The invention provides a synthesis method of a paeoniflorin derivative shown in formula III, which can obviously reduce the consumption of a reaction solvent, shorten the reaction time, has the characteristics of economy, saving, simple operation, mild conditions and greatly improved reaction yield, is suitable for carrying out wider structural modification on paeoniflorin, and can meet the requirement of industrialization.

Description

Method for synthesizing paeoniflorin derivative

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of a paeoniflorin derivative.

Background

Paeoniflorin, a major component of Total Glucosides of Paeony (TGP), has been used in the clinical treatment of rheumatoid arthritis. However, TGP has some disadvantages such as slow onset of action, large individual difference in therapeutic effect, low bioavailability, etc. It has also been found in clinical practice that some patients experience gastrointestinal reactions such as diarrhea and loss of appetite when the oral dosage is increased. Therefore, the paeoniflorin is structurally modified to improve the curative effect and the bioavailability, and is more beneficial to the recovery of patients.

Therefore, the prior art provides an esterification method using 4-Dimethylaminopyridine (DMAP) as a catalyst, and although the paeoniflorin-6-O' -benzene sulfonate compound with better curative effect is synthesized by the method, the method has the defects of large organic solvent dosage, addition of pyridine with certain reproductive toxicity and acylating reagent acyl chloride in a slow dropwise manner, low yield and the like, and is not beneficial to environmental protection and industrial production. Therefore, an efficient and economic paeoniflorin esterification method is developed, and convenience is brought to the search of a paeoniflorin derivative with a better curative effect and subsequent industrial production.

Disclosure of Invention

The present invention has been made to solve at least one of the above-mentioned problems occurring in the prior art. Therefore, the invention provides a synthesis method of paeoniflorin derivatives, which can obviously reduce the dosage of reaction solvents, shorten the reaction time and greatly improve the reaction yield and content.

Specifically, the invention provides a synthesis method of a paeoniflorin derivative shown in a formula III, which comprises the following reaction route:

specifically, the synthesis method comprises the following steps: dissolving paeoniflorin or a crude product of paeoniflorin in an organic solvent, adding a metal catalyst for catalysis, and carrying out esterification reaction under the action of an acid-binding agent and acyl chloride R-Cl to obtain the paeoniflorin derivative.

Wherein R-Cl is selected from C ₁ ～C ₂₀ Substituted and unsubstituted acyl chloride and C ₁ ～C ₂₀ Substituted and unsubstituted sulfonyl chlorides.

In some embodiments of the invention, R is selected from:

in some embodiments of the present invention, the crude paeoniflorin is derived from a natural plant extract, such as at least one extract from radix Paeoniae alba, radix Paeoniae Rubra, cortex moutan, dog head, peony root, and purple peony, wherein the paeoniflorin content is greater than 40%.

In the invention, the paeoniflorin is catalyzed by adopting a metal catalyst

The esterification reaction can obviously improve the reaction efficiency and the product yield; the acyl chloride can be added at one time without dropwise addition, in order to realize paeoniflorin derivative

The synthesis of (a) provides a convenient industrial production scheme.

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

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

Compared with the existing synthesis process, the dosage of acyl chloride is reduced due to the efficient selective synthesis of the catalyst, and the slow dropwise addition within at least 3 hours in the prior art is changed into the one-time addition in the acyl chloride feeding mode, so that the industrial production is facilitated.

In some more preferred embodiments of the invention, the metal catalyst is selected from C ₁ ～C ₄ Alkyl tin halides, aryl tin halides, C ₁ ～C ₄ Alkyl tin oxide of (2) ₁ ～C ₄ Or a combination thereof; further preferably, the metal catalyst is selected from dimethyltin dichloride, diethyltin dichloride, dibutyltin dichloride, dimethyltin sulfide, dimethyltin oxide, or a combination thereof.

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

In some more preferred embodiments of the present invention, the acid scavenger is at least one selected from the group consisting of triethylamine, N' -diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, and sodium bicarbonate.

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

In some more preferred embodiments of the present invention, the mass-to-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; more preferably 1: (5-7) g/mL. Compared with the prior art in which the dosage of the organic solvent is 20-80 times of the weight of the paeoniflorin, the volume of the organic solvent is only 2-10 times of the weight of the paeoniflorin, and the dosage of the reaction organic solvent is obviously reduced.

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

In some more preferred embodiments of the present invention, the temperature of the esterification reaction is from-40 ℃ to 70 ℃; more preferably 20 to 30 ℃.

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

In some more preferred embodiments of the present invention, after said esterification, a purification step is further included; further preferably, the purification is carried out in an extraction and concentration mode; still more preferably, the specific operations of the purification are: adding an extracting agent into the esterification product for extraction, and concentrating an organic layer to obtain the paeoniflorin-6-O' -benzene sulfonate.

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

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

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

The invention has the beneficial effects that:

the synthesis method disclosed by the invention has the characteristics of less catalyst and organic solvent consumption, short reaction time, no need of dropwise adding raw materials and the like, namely has the characteristics of economy, simplicity in operation and mild conditions, can greatly improve the reaction yield, is suitable for carrying out wider paeoniflorin structural modification, and can meet the industrial requirement.

Drawings

The invention is further described with reference to the following figures and examples, in which:

FIG. 1 is a mass spectrum of the product of example 1 of the present invention.

FIG. 2 is a hydrogen spectrum of the product of example 1 of the present invention.

FIG. 3 is a carbon spectrum of the product of example 1 of the present invention.

FIG. 4 is a liquid chromatogram of example 1 and comparative example 1 of the present invention.

FIG. 5 is a liquid chromatogram of comparative example 2 and comparative example 3 of the present invention.

Detailed Description

The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and other embodiments obtained by those skilled in the art without inventive efforts are within the protection scope of the present invention based on the embodiments of the present invention.

Example 1

The paeoniflorin-6-O' -benzene sulfonate is prepared by the following specific steps:

dissolving 6g of pure paeoniflorin (the content is 98%) in 25mL of acetone at room temperature, adding 0.04g of dibutyltin dichloride for activation for 10min after complete dissolution, then sequentially adding 3.3mL of N, N' -Diisopropylethylamine (DIPEA) and 1.6mL of benzenesulfonyl chloride for reaction for 2h, detecting by TLC (a developing agent ratio is: chloroform: absolute ethanol = 8) for reaction, extracting with 60mL of ethyl acetate and 30mL of water after complete reaction, separating liquid, and concentrating until dry to obtain 7.6g of white solid, wherein the yield is 98.2% and the content is 93.1% according to molar weight. The mass spectrum, hydrogen spectrum and carbon spectrum of the product are respectively shown in figure 1, figure 2 and figure 3. The results of the liquid phase assay are shown in FIG. 4.

Example 2

The paeoniflorin-6-O' -p-methylbenzenesulfonate is prepared by the following specific steps:

adding dry ice into ethylene glycol to prepare a cooling bath at about-10 ℃, dissolving 6g of paeoniflorin (with the content of 98%) in 25mL of acetone, then placing the solution in the cooling bath, adding 0.06g of dibutyltin dichloride for activation for 10min after the paeoniflorin is completely dissolved, then sequentially adding 3.3mL of N, N' -Diisopropylethylamine (DIPEA) and 2.4g of p-toluenesulfonyl chloride for reaction for 3h, carrying out TLC detection reaction, extracting and separating the solution by using 70mL of ethyl acetate and 35mL of water after the reaction is completely finished, concentrating the solution until the solution is dried to obtain 7.6g of white solid, wherein the yield is 95.8% according to molar weight and the content is 90%.

Example 3

In this example, paeoniflorin-6-O' -2-fluorobenzenesulfonate was prepared by the following steps:

dissolving 10g of paeoniflorin (the content is 98%) in 30mL of N, N' -Dimethylformamide (DMF) at room temperature, adding 0.10g of dimethyltin dichloride to activate for 10min after complete dissolution, sequentially adding 4.3g of potassium carbonate and 4.1g of 2-fluorobenzenesulfonyl chloride to react for 3.5h, detecting by TLC, extracting and separating by using 100mL of ethyl acetate and 70mL of water after complete reaction, and concentrating to dryness to obtain 11.2g of white solid, wherein the yield is 84.1% and the content is 91%.

Example 4

The paeoniflorin-6-O' -4-chlorobenzenesulfonate prepared by the embodiment comprises the following specific processes:

dissolving 10g of paeoniflorin (with the content of 98%) in 50mL of acetonitrile at room temperature, adding 0.10g of dimethyltin dichloride to activate for 10min after complete dissolution, sequentially adding 3.5mL of triethylamine and 4.1g of 4-fluorobenzenesulfonyl chloride to react for 1h, detecting by TLC, extracting and separating by using 90mL of ethyl acetate and 50mL of water after complete reaction, and concentrating to dryness to obtain 11.8g of white solid with the yield of 87.1% and the content of 91%.

Example 5

The paeoniflorin-6-O' -3-methoxybenzenesulfonate is prepared by the following specific steps:

dissolving 10g of paeoniflorin (the content is 98%) in 50mL of Tetrahydrofuran (THF) at room temperature, adding 4g of dimethyltin dichloride to activate for 10min after complete dissolution, sequentially adding 3.5mL of triethylamine and 2.95mL of 3-methoxybenzenesulfonyl chloride to react for 0.5h, detecting by TLC (thin layer chromatography), extracting and separating by using 90mL of ethyl acetate and 50mL of water after complete reaction, and concentrating to dryness to obtain 13g of white solid, wherein the yield is 96.3% and the content is 95.6%.

Example 6

In this example, paeoniflorin-6-O' -4-iodobenzene sulfonate was prepared by the following steps:

dissolving 10g of paeoniflorin (the content is 98%) in 40mL of acetone under the condition of water bath at 40 ℃, adding 0.2g of diethyl tin dichloride for activation for 10min after complete dissolution, sequentially adding 3.5mL of triethylamine and 9.4g of 4-iodobenzene sulfonyl chloride for reaction for 5h, detecting by TLC (thin layer chromatography), extracting and separating by using 100mL of ethyl acetate and 50mL of water after complete reaction, and concentrating to dryness to obtain 14.5g of white solid with the yield of 93.3% and the content of 90%.

Example 7

The paeoniflorin-6-O' -3-phenylpropionate is prepared by the following specific steps:

dissolving 6g of paeoniflorin (with the content of 98%) in 30mL of acetone at the temperature of 0 ℃, adding 0.07g of dimethyl tin sulfide for activation for 10min after complete dissolution, sequentially adding 3mL of triethylamine and 1.9mL of 3-phenylpropionyl chloride for reaction for 5h, detecting by TLC (thin layer chromatography), extracting and separating liquid by using 60mL of ethyl acetate and 30mL of water after complete reaction, and concentrating to be dry to obtain 12.6g of white solid with the yield of 98.8% and the content of 93%.

Example 8

dissolving 10g of paeoniflorin (the content is 98%) in 40mL of acetone under the condition of water bath at 25 ℃, adding 0.07g of dimethyl tin oxide to activate for 10min after complete dissolution, sequentially adding 4.3mL of triethylamine and 2.7mL of benzenesulfonyl chloride to react for 5h, detecting by TLC, extracting and separating by using 100mL of ethyl acetate and 50mL of water after complete reaction, and concentrating until the mixture is dried to obtain 11g of white solid with the yield of 85.1% and the content of 80%.

Example 9

dissolving 10g of paeoniflorin (the content is 98%) in 60mL of acetonitrile under the condition of 65 ℃ water bath, adding 0.08g of dimethyl tin oxide to activate for 10min after complete dissolution, sequentially adding 4.3mL of triethylamine and 2.7mL of benzene sulfonyl chloride to react for 1h, detecting by TLC, extracting and separating by using 100mL of ethyl acetate and 50mL of water after complete reaction, and concentrating until the mixture is dried to obtain 11.7g of white solid, wherein the yield is 90.6% and the content is 85%.

Example 10

dissolving 10g of paeoniflorin extract (the content is 44.7%) in 60mL of acetonitrile at room temperature, adding 0.04g of dimethyl tin oxide to activate for 10min after complete dissolution, sequentially adding 2.3mL of triethylamine and 1.7mL of benzenesulfonyl chloride to react for 6h, detecting by TLC, extracting and separating by using 100mL of ethyl acetate and 50mL of water after complete reaction, and concentrating to dry to obtain 4.4g of white solid with the yield of 76.2% and the content of 36%.

Example 11

dissolving 10g of crude paeoniflorin (with the content of 66.3%) in 60mL of acetonitrile at room temperature, adding 0.07g of dimethyl tin oxide to activate for 10min after complete dissolution, sequentially adding 4mL of triethylamine and 2mL of benzene sulfonyl chloride to react for 10h, detecting by TLC, extracting and separating by using 110mL of ethyl acetate and 60mL of water after complete reaction, and concentrating to dry to obtain 6g of white solid with the yield of 79.5% and the content of 57%.

Example 12

In this example, a crude paeoniflorin product is prepared, and the specific process is as follows:

collecting 50g of paeoniflorin extract (paeoniflorin content is 44.7%), adding 100mL of isopropanol, dissolving, adding 150g of neutral alumina, stirring, adsorbing, adding adsorbed neutral alumina into a chromatographic column, eluting with 200mL of isopropanol, collecting eluate, and concentrating to obtain 28.4g of paeoniflorin intermediate with paeoniflorin content of 78.3%. The obtained paeoniflorin intermediate was dissolved using 100mL of a solvent (chloroform: ethanol = 5) and 450g of silica gel was packed, and the eluent was chloroform: ethanol =9:1, eluting by silica gel column chromatography, eluting by 2.75L in total, collecting eluent, and concentrating under reduced pressure to obtain 23.7g of crude paeoniflorin with the content of 90.5%.

Example 13

under the condition of room temperature, 100kg (the content is 90%) of crude paeoniflorin is stirred and dissolved completely in a reaction concentration tank by using 312kg of acetone, 1kg of dimethyltin dichloride is added into the reaction tank to be activated for 15min, 27.6kg of triethylamine and 36.7kg of benzenesulfonyl chloride are sequentially added to react for 2h, TLC detection reaction is carried out in the reaction process, after the reaction is completed, 1000kg of ethyl acetate and 500kg of water are added into the reaction concentration tank to be stirred and extracted for 5min, standing is carried out for 1h for liquid separation, an organic layer is reserved and concentrated to be dry, and the solid content is measured at the same time: 300mL of the organic layer solution was concentrated to dryness to give 23.3g, and the organic layer concentration was about 0.078g/mL (0.078 kg/L), and the volume of the organic layer solution after conversion to acetone and ethyl acetate was 1506L, whereby the organic layer contained about 117.5kg of the product as a white solid in a yield of 91.1% and a content of 82%.

Comparative example 1

The paeoniflorin-6-O' -benzene sulfonate is prepared according to the optimal conditions in the prior art by the specific process:

6g of paeoniflorin (content: 98%) is dissolved in a mixed solution of 36mL of chloroform and 8mL of pyridine at room temperature, and then 50mg of 4-dimethylaminopyridine is added for activation for 30min. Dissolving 3.2mL of benzene sulfonyl chloride in 4mL of dichloromethane within 3h, then dripping into the reaction solution for reaction, continuing the reaction for 6.5h after the dripping is finished, and detecting the reaction by TLC in the reaction process. After the reaction, after concentrating to an oily substance, 60mL of ethyl acetate was added and extracted three times, 60mL of 1M hydrochloric acid was added each time, and the remaining organic layer was concentrated to 6.1g of a yellow oily viscous substance with a yield of 78.8% and a content of 80.1%. The results of the liquid phase assay are shown in FIG. 4.

Comparative example 2

The comparative example prepares paeoniflorin-6-O' -benzene sulfonate, and the specific process is as follows:

dissolving 6g of crude paeoniflorin (the content is 90.5%) in 25mL of acetone at room temperature, adding 0.04g of dibutyltin dichloride for activation for 10min after complete dissolution, sequentially adding 3.3mL of N, N' -Diisopropylethylamine (DIPEA) and 1.6mL of benzenesulfonyl chloride for reaction for 2h, detecting by TLC, extracting with 60mL of ethyl acetate and 30mL of water after complete reaction, separating liquid, and concentrating until the mixture is dried to obtain 7.5g of white solid, wherein the yield is 91.1% and the content is 89.6%. The liquid phase detection results are shown in FIG. 5.

Comparative example 3

6g of crude paeoniflorin (90.5% in content) is dissolved in a mixed solution of 36mL of chloroform and 8mL of pyridine at room temperature, and then 50mg of 4-dimethylaminopyridine is added for activation for 30min. Dissolving 3.2mL of benzene sulfonyl chloride in 4mL of dichloromethane within 3h, then dripping into the reaction solution for reaction, continuing to react for 6.5h after dripping is finished, and detecting the reaction by TLC in the reaction process. After the reaction, after concentrating to an oily substance, 60mL of ethyl acetate was added and extracted three times, 60mL of 1M hydrochloric acid was added each time, and the remaining organic layer was concentrated to 5.4g 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 FIG. 5.

Table 1 summary of the results of example 1 and comparative examples

Compared with the comparative examples 1-3, and the combination of fig. 4 and fig. 5, the content and yield of the technology of the invention are better than those of the prior art after the pure paeoniflorin is reacted by different reaction methods: specifically, the content of the pure paeoniflorin is 93.1% after the reaction by the technical method of the invention, the yield is 98.2%, wherein 12 impurity peaks with impurity content of more than 0.05% are provided, 10 impurity peaks with impurity content of more than 0.1% are provided, and 80.1% impurity peak with impurity content of more than 0.05% and 78.8% yield are provided after the reaction by the prior art, 21 impurity peaks with impurity content of more than 0.05% are provided, and 18 impurity peaks with impurity content of more than 0.1% are provided. In the self-made paeoniflorin, the technical method is also better than the prior art; the invention has better tolerance to the reaction raw materials, and the reaction product has the characteristics of high content and less impurities, thereby being beneficial to industrial production and reducing the production cost.

In addition, in examples 1 to 9, the catalyst activation time and the addition time of the intermediate materials such as acyl chloride, acid binding agent and the like are obviously shorter than those of comparative example 1, the reaction solvent required by comparative example 1 is about 2 times of that required by example 1, and a second solvent pyridine with certain reproductive toxicity and high boiling point is also used in the reaction process of comparative example 1; in addition, in the aspect of adding acyl chloride, the mode of adding acyl chloride at one time is adopted in examples 1-9, while the mode of dropwise adding slowly is adopted in comparative example 1, the time is required to be 3 hours, so that the whole reaction time is longer. In addition, the invention adopts organic metal catalyst, can raise the reaction efficiency apparently, shorten reaction time; whereas example 1 is improved by 10% or more in reaction yield compared to comparative example 1. Therefore, the technical scheme of the invention obviously reduces the using amount of the reaction solvent, reduces the production cost, has short production process time, is environment-friendly and high in safety, and greatly improves the reaction yield.

The embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.

Claims

1. A method for synthesizing a paeoniflorin derivative of formula III, which is characterized in that: the method comprises the following steps: dissolving paeoniflorin or a crude product of paeoniflorin in an organic solvent, adding a metal catalyst for catalysis, and carrying out esterification reaction under the action of an acid-binding agent and acyl chloride R-Cl to obtain a paeoniflorin derivative;

wherein the crude paeoniflorin is derived from natural plant extract, wherein the content of paeoniflorin is more than 40%;

the R-Cl is selected from C ₁ ～C ₂₀ Substituted and unsubstituted acyl chlorides; preferably C ₁ ～C ₂₀ Substituted and unsubstituted sulfonyl chlorides.

2. The method for synthesizing paeoniflorin derivative according to claim 1, wherein: based on 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 paeoniflorin derivatives according to claim 1, wherein: the metal catalyst is selected from C ₁ ～C ₄ Alkyl tin halides, aryl tin halides, C ₁ ～C ₄ Alkyl tin oxide of (2) ₁ ～C ₄ Or a combination thereof.

4. The method for synthesizing paeoniflorin derivatives according to claim 1 or 3, wherein: based on 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 paeoniflorin derivative according to claim 1, wherein: the acid-binding agent is selected from triethylamine, N' -diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate or a combination thereof.

6. The method for synthesizing paeoniflorin derivative according to claim 1, wherein: the organic solvent is selected from tetrahydrofuran, acetone, methyl ethyl ketone, N' -dimethylformamide, acetonitrile, 1, 4-dioxane, dimethyl sulfoxide or a combination thereof.

7. The method for synthesizing paeoniflorin derivatives according to claim 1 or 6, wherein: the mass volume ratio of the paeoniflorin to the organic solvent is 1: (1-20) g/mL.

8. The method for synthesizing paeoniflorin derivative according to claim 1, wherein: the temperature of the esterification reaction is-40 ℃ to 70 ℃.

9. The method for synthesizing paeoniflorin derivatives according to claim 1 or 8, wherein: the esterification reaction time is 0.5 h-10.0 h.

10. The method for synthesizing paeoniflorin derivative according to claim 1, wherein: after the esterification reaction, a purification step is also included.