CN112745280A - Chlorogenic acid derivative for clearing away heat and toxic materials and preparation method thereof - Google Patents
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Abstract
The invention discloses a chlorogenic acid derivative for clearing away heat and toxic materials and a preparation method thereof, belonging to the technical field of chemical drug synthesis and preparation; the preparation method of the derivative comprises the following steps: under the action of alkali in an anhydrous environment, esterifying chlorogenic acid and formic acid, sequentially reacting with dimethyl sulfate and 1- (2-aminoethyl) pyrrolidine to obtain a crude product, and further purifying and separating the crude product through a silica gel column to obtain a chlorogenic acid derivative; the invention improves the structure of chlorogenic acid, finds out a compound with simpler structure and stronger activity, and has wide application in the effects of clearing away heat and toxic materials, resisting bacteria and diminishing inflammation and the like; the preparation method provided by the invention has the advantages of simple and easily-obtained raw materials, mild reaction conditions, simple and convenient post-treatment, wide applicable substrate range and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis and preparation, and relates to a chlorogenic acid derivative for clearing away heat and toxic materials and a preparation method thereof.
Background
Chlorogenic acid is a phenylpropanoid compound generated by a shikimic acid pathway in the aerobic respiration process of a plant body, and is always highly concerned by students after being successfully extracted from apples for the first time in the 50 th of the 20 th century. Research shows that chlorogenic acid has the efficacy of clearing heat and removing toxicity and is often used in traditional Chinese medicine preparations for clearing heat and removing toxicity. However, the chlorogenic acid has carboxyl in the structure, so that the medicine has acidity, can cause great stimulation to gastric mucosa when the acidic medicine is orally taken, and can cause stimulation to skin or be difficult to be transdermally absorbed when the chlorogenic acid is externally used, so that the biological activity of the chlorogenic acid cannot be fully utilized.
Disclosure of Invention
In order to solve the technical problems, the invention provides a chlorogenic acid derivative for clearing away heat and toxic materials, which has a molecular structure shown in a formula (I):
another object of the present invention is to provide a method for preparing chlorogenic acid derivatives with effects of clearing away heat and toxic materials, comprising the following steps:
(1) under the protection of nitrogen, dissolving chlorogenic acid in a tetrahydrofuran solution at room temperature, adding formic acid, raising the temperature to 60-100 ℃, stirring and reacting for 8-15 h, detecting by TLC to finish the reaction, washing the filtrate with saturated saline solution and water for multiple times, extracting with ethyl acetate, combining organic layers, drying with anhydrous calcium chloride, dissolving the dried product in dichloromethane, adding dimethyl sulfate and sodium hydroxide, stirring and dissolving, raising the temperature to 40-60 ℃, performing reflux reaction for 3-7 h, adding a large amount of ice water to quench the reaction, extracting with ethyl acetate, combining the organic layers, drying with anhydrous sodium sulfate, and performing reduced pressure distillation to obtain a compound A;
(2) dissolving a compound A in an organic solvent, adding 1- (2-aminoethyl) pyrrolidine, adding a condensing agent, heating to 60-90 ℃, carrying out reflux reaction for 3-10 h, after TLC detection reaction is finished, cooling to room temperature, adding a sodium hydroxide solution dropwise, stirring for dissolving reaction for 0.5-1 h, washing filtrate with a hydrochloric acid solution, a saturated saline solution and water, extracting with ethyl acetate, combining organic layers, concentrating under reduced pressure to obtain an extract, and carrying out silica gel column elution chromatography on the extract to obtain a target product;
in the step (1), the molar ratio of chlorogenic acid to formic acid is 1 (1.5-3.5);
the molar ratio of the chlorogenic acid to the dimethyl sulfate is 1 (1.5-3.5);
in the step (2), the molar ratio of the compound A to the 1- (2-aminoethyl) pyrrolidine is 1: (1.0-1.8);
the organic solvent is dichloromethane, carbon tetrachloride, acetone, acetonitrile or diethyl ether;
the condensing agent is 1-hydroxybenzotriazole, carbonyl-1, 1-diimidazole alkane, 4-dimethylamino pyridine or 1- (3-dimethylamino propyl) -3-ethyl carbodiimide hydrochloride;
the silica gel column eluent is a mixed solution of ethyl acetate and methanol, wherein the volume ratio of ethyl acetate to methanol is (10-50): 1.
According to a preferred embodiment of the above preparation method, the method comprises the following steps:
(1) under the protection of nitrogen, dissolving 20g of chlorogenic acid in tetrahydrofuran solution at room temperature, adding 9.1g of formic acid, raising the temperature to 100 ℃, stirring for reaction for 8 hours, detecting by TLC (thin layer chromatography), washing the filtrate with saturated saline solution and water for multiple times, extracting with ethyl acetate, combining organic layers, drying with anhydrous calcium chloride, dissolving the dried product in dichloromethane, adding dimethyl sulfate and sodium hydroxide, stirring for dissolution, raising the temperature to 60 ℃, refluxing for reaction for 7 hours, adding a large amount of ice water for quenching reaction, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, and carrying out reduced pressure distillation to obtain a compound A;
(2) dissolving 14g of the compound A in dichloromethane, adding 6.2g of 1- (2-aminoethyl) pyrrolidine, adding 1-hydroxybenzotriazole, heating to 60 ℃, carrying out reflux reaction for 3h, after TLC detection reaction is finished, adding saturated sodium carbonate to quench reaction, washing filtrate with hydrochloric acid solution, saturated saline solution and water, extracting with ethyl acetate, combining organic layers, concentrating under reduced pressure to obtain extract, carrying out elution chromatography on the extract through a silica gel column, collecting eluent which is a mixed solution of ethyl acetate and methanol in a volume ratio of 10:1, and concentrating the eluent under reduced pressure to obtain the target product.
Compared with the prior art, the invention has the beneficial effects that:
the invention adopts natural plant extract chlorogenic acid to modify the structure of the chlorogenic acid to obtain a chlorogenic acid derivative with amido bond; the pathological experiment shows that the chlorogenic acid derivative has better inhibitory activity to escherichia coli, vancomycin intermediate drug-resistant staphylococcus aureus and staphylococcus epidermidis, particularly shows more remarkable inhibitory activity to escherichia coli, has the minimum inhibitory concentration of 4 mug/mL, and has better inhibitory effect than the chlorogenic acid used alone; has effect in resisting herpes simplex virus HSV 1; the compound preparation has the same inhibiting effect on mouse ear swelling caused by croton oil as qingkailing injection; and has reducing effect on rabbit fever caused by typhoid fever and paratyphoid A-B triple vaccine; and the toxicity to Vero cells is lower than that of qingkailing injection.
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FIG. 1: nuclear magnetic resonance hydrogen spectrum of chlorogenic acid derivative for clearing away heat and toxic material of example 1.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1
(1) Under the protection of nitrogen, dissolving 20g of chlorogenic acid in tetrahydrofuran solution at room temperature, adding 9.1g of formic acid, raising the temperature to 100 ℃, stirring for reaction for 8 hours, detecting by TLC (thin layer chromatography), washing the filtrate with saturated saline solution and water for multiple times, extracting with ethyl acetate, combining organic layers, drying with anhydrous calcium chloride, dissolving the dried product in dichloromethane, adding dimethyl sulfate and sodium hydroxide, stirring for dissolution, raising the temperature to 60 ℃, refluxing for reaction for 7 hours, adding a large amount of ice water for quenching reaction, extracting with ethyl acetate, combining organic layers, drying with anhydrous sodium sulfate, and carrying out reduced pressure distillation to obtain a compound A;
(2) dissolving 14g of the compound A in dichloromethane, adding 6.2g of 1- (2-aminoethyl) pyrrolidine, adding 1-hydroxybenzotriazole, heating to 60 ℃, carrying out reflux reaction for 3h, after TLC detection reaction is finished, adding saturated sodium carbonate to quench reaction, washing filtrate with hydrochloric acid solution, saturated saline solution and water, extracting with ethyl acetate, combining organic layers, concentrating under reduced pressure to obtain extract, carrying out elution chromatography on the extract through a silica gel column, collecting eluent which is a mixed solution of ethyl acetate and methanol in a volume ratio of 10:1, and concentrating the eluent under reduced pressure to obtain the target product. The yield was 79.30%.
And (3) nuclear magnetic resonance hydrogen spectrum detection:
the sample was placed in a sample tube, and 0.5ml of DCL3 (deuterated chloroform) was injected into the sample tube with a syringe to dissolve the sample sufficiently. The sample and the reagent are required to be fully mixed, the solution is clear and transparent, and has no suspended matters or other impurities, and a nuclear magnetic resonance hydrogen spectrogram is obtained through nuclear magnetic resonance identification, and the result is shown in figure 1.
EXAMPLE 2 pharmacodynamic test of the Compounds of the invention for clearing Heat and detoxicating
1. Antibacterial Activity test of the drug of the present invention
Test strains: staphylococcus aureus (a), escherichia coli (b), vancomycin intermediate drug-resistant staphylococcus aureus (c), staphylococcus epidermidis (d), streptococcus pneumoniae (e), klebsiella pneumoniae (f) and salmonella (g).
Dissolving the chlorogenic acid derivative in absolute ethyl alcohol, diluting the solution to 1000 mu g/mL by using tryptone soybean broth culture solution, and continuously diluting the solution by using the culture solution to ensure that the concentration of the medicine is 256-0.25 mu g/mL to obtain an experimental solution; then preparing qingkailing injection with the concentration range of 256-0.25 mug/mL as a positive control group (control group 1); chlorogenic acid was prepared as control 2 in the same manner. Adding liquid medicine with the concentration range of 256-0.25 mu g/mL and 100 mu L of bacterial liquid into each hole of a 96-hole plate, wherein the concentration of the final medicine is 5 multiplied by 104CFU was incubated for 20 hours in a 37 ℃ incubator after sealing a 96-well plate with a tryptone soy broth medium as a negative control (TSB medium, 100. mu.L each of the broth) and a TSB broth medium without the broth as a blank control (TSB medium, 200. mu.L each). Measuring absorbance at 625nm of each well, and comparing the absorbance with blank OD625Wells with consistent values were considered to have no significant growth of bacteria. The lowest concentration of drug at which bacteria do not significantly grow is the minimum inhibitory concentration MIC of the compound of the invention.
Table 1 in vitro antimicrobial activity assay of compounds of the invention
The data in table 1 show that the chlorogenic acid derivative has good inhibitory activity to escherichia coli, vancomycin intermediate drug-resistant staphylococcus aureus and staphylococcus epidermidis, particularly shows more remarkable inhibitory activity to escherichia coli, has the minimum inhibitory concentration of 4 mug/mL, and has better inhibitory effect than the chlorogenic acid used alone.
2. Test for antiviral Activity of Compounds of the present invention
(1) Effect of Compounds of the invention on cytotoxicity
Respectively inoculating the chlorogenic acid derivative (experimental group), qingkailing injection (control group 3) and diluted liquid medicine of chlorogenic acid (control group 4) with different dilution concentrations (1: 20-1: 90) into Vero cells with formed monolayer cells, wherein 4 cells in each group are synchronously arranged in parallel in a cell control group (control group 1) and a blank control group (Hanks liquid replaces liquid medicine, and control group 2) and is added with Eagles maintaining liquid. Incubate at 37 ℃ in an incubator, observe the cellular toxic response daily, calculate the maximum non-toxic concentration (TD0), and repeat the assay. The results are shown in Table 3.
TABLE 2 toxic Effect of the Compounds of the invention on Vero cells
Note: "+ + + + + +", "+" indicates that the 4-tube cells are not toxic, and "-" indicates that the 4-tube cells are toxic.
The data in table 2 show that the chlorogenic acid derivative, the chlorogenic acid and the qingkailing injection stock solution have obvious toxicity to Vero cells, and when the two stock solutions except the chlorogenic acid are diluted to more than 40 times by the same volume, the toxicity of the medicine to the cells is weak or even disappears; when the concentration of the chlorogenic acid derivative stock solution is diluted to 1:40, the chlorogenic acid derivative stock solution has no toxicity to cells, but the qingkailing injection still has toxicity, which indicates that the toxicity of chlorogenic acid derivative Vero cells is less than that of the qingkailing injection.
(2) Virulence test of viruses on cells
HSV1 form was serially diluted 10-fold with Hanks' solution from 10-1～10-9. Inoculating the diluted virus into Vero cell tubes, synchronously arranging cell control tubes in parallel, and adding sufficient Eagles maintenance liquid. The cells were incubated at 37 ℃ and observed daily for cytopathic effects, and half of the cell infectivity (TCID50) was calculated by the Read-maench method. The results are shown in Table 3.
TABLE 3 half infected cell Mass (TCID) of Virus50)
| Virus | HSV1 |
| TCID50 | 10-7 |
(3) Test for antiviral Effect of Compounds of the present invention
Get 10-7TCID50Inoculating HSV1 type virus solution into Vero cell tube, adsorbing for 1 hr, and washing to remove virus solution. Chlorogenic acid (experimental group) and qingkailing injection (control group 3) with different concentrations (1: 20-1: 90) are respectively added, and after 45 minutes of adsorption, Eagles maintaining liquid is added. A virus control group (control group 1), a cell control group (control group 2) and chlorogenic acid (control group 4) are synchronously arranged in parallel, and Hanks liquid is used for replacing liquid medicine as a blank control. The cells were incubated at 37 ℃ and observed day by day for cytopathic effects. The test can be terminated when the virus control group shows ++++ - +++++ lesions. And after repeating the experiment, the minimum effective concentration (MIC) for inhibiting the virus action was calculated. The results are shown in Table 4.
TABLE 4 in vitro antiviral Activity of the inventive drugs and qingkailing injection
Note: "-" indicates that 4 tubes of cells were not diseased, "+ (-) -," + "," + + + + + + + + "indicates that 4 tubes of cells were diseased from light to heavy.
The data in Table 4 show that the three drugs have different degrees of intracellular lesion inhibition effects on HSV1, wherein the chlorogenic acid derivative has better inhibition effect, is superior to positive drug qingkailing injection, and has better inhibition effect than single action chlorogenic acid.
3. Anti-inflammatory Effect test of the Compound of the present invention
Healthy male Kunming mice are selected and randomly grouped as follows: model group (control group 1), qingkailing injection group (control group 2), chlorogenic acid group (control group 3) and experimental group. Each group of animals is dosed once a day, the model group is fed with distilled water with the same volume, other groups are fed with corresponding medicines, the animals are fed for three days continuously, after the last dose is 1h, the left ear of each animal is coated with 0.02mL of croton oil, the right ear is not coated with normal ear, the animals are killed after inflammation for 4h, two ears are cut, the ears are punched at the same part of the ears by a puncher with the diameter of 0.8cm, the weights of the two ears are respectively weighed, and the weight difference value is used as the swelling degree. The results are shown in Table 5.
The inhibition rate of ear swelling is%
Table 5 effect of the compounds of the present invention on croton oil-induced ear swelling in mice
| Group of | Dosage (g/kg) | Degree of swelling | Swelling inhibition ratio (%) |
| Control group 1 | － | 33.66±3.24 | － |
| Control group 2 | 30.0 | 22.79±2.18 | 52.03 |
| Control group 3 | 30.0 | 28.21±3.26 | 30.22 |
| Experimental group | 30.0 | 23.84±2.21 | 47.81 |
The data in table 5 show that compared with the model group, the chlorogenic acid derivative can obviously inhibit mouse ear swelling caused by croton oil, the inhibition effect of the chlorogenic acid derivative is equivalent to that of qingkailing injection, and the chlorogenic acid derivative is superior to that of chlorogenic acid when the chlorogenic acid derivative is used alone.
4. Test for antipyretic Effect of the Compound of the present invention
The influence of the drug of the invention on a rabbit fever model caused by typhoid fever and paratyphoid A-B triple vaccine is tested. Healthy rabbits were selected and randomly grouped. Continuously measuring the anal temperature for 3 times, each time for 3min, at an interval of 1h, taking the average value of the 3 results as the basal body temperature, then injecting 1mL/kg of the triple vaccine of typhoid fever and paratyphoid A, B in the ear vein of the rabbit, and feeding when the anal temperature rises to 0.5 ℃. The experimental group is fed with 15g/kg of chlorogenic acid derivative, the model group (control group 1) is fed with distilled water with the same amount, the positive control group (control group 2) is qingkailing injection, and the chlorogenic acid group (control group 3) is fed with 30g/kg of chlorogenic acid, and the temperature is measured once every 1h and continuously for 6 h. The body temperature changes of the animals in each group were calculated at different times after the administration, and the experimental results are shown in table 6.
TABLE 6 antipyretic Effect of Compounds of the invention
The data in Table 6 show that compared with the model control group, the three medicines can reduce the body temperature of the rabbits infected with the typhoid fever, the paratyphoid A and the B triple bacterins, wherein the chlorogenic acid derivative has equivalent effect with the qingkailing injection and is far better than the chlorogenic acid cooling effect with single action.
Claims (3)
1. A chlorogenic acid derivative for clearing away heat and toxic materials, which has a molecular structure of formula (I):
2. a preparation method of chlorogenic acid derivatives for clearing away heat and toxic materials is characterized by comprising the following steps:
(1) under the protection of nitrogen, dissolving chlorogenic acid in a tetrahydrofuran solution at room temperature, adding formic acid, raising the temperature to 60-100 ℃, stirring and reacting for 8-15 h, detecting by TLC to finish the reaction, washing the filtrate with saturated saline solution and water for multiple times, extracting with ethyl acetate, combining organic layers, drying with anhydrous calcium chloride, dissolving the dried product in dichloromethane, adding dimethyl sulfate and sodium hydroxide, stirring and dissolving, raising the temperature to 40-60 ℃, performing reflux reaction for 3-7 h, adding a large amount of ice water to quench the reaction, extracting with ethyl acetate, combining the organic layers, drying with anhydrous sodium sulfate, and performing reduced pressure distillation to obtain a compound A;
(2) dissolving a compound A in an organic solvent, adding 1- (2-aminoethyl) pyrrolidine, adding a condensing agent, heating to 60-90 ℃, carrying out reflux reaction for 3-10 h, after TLC detection reaction is finished, cooling to room temperature, adding a sodium hydroxide solution dropwise, stirring for dissolving reaction for 0.5-1 h, washing filtrate with a hydrochloric acid solution, a saturated saline solution and water, extracting with ethyl acetate, combining organic layers, concentrating under reduced pressure to obtain an extract, and carrying out silica gel column elution chromatography on the extract to obtain a target product;
in the step (1), the molar ratio of chlorogenic acid to formic acid is 1 (1.5-3.5);
the molar ratio of the chlorogenic acid to the dimethyl sulfate is 1 (1.5-3.5);
in the step (2), the molar ratio of the compound A to the 1- (2-aminoethyl) pyrrolidine is 1: (1.0-1.8);
the organic solvent is dichloromethane, carbon tetrachloride, acetone, acetonitrile or diethyl ether;
the condensing agent is 1-hydroxybenzotriazole, carbonyl-1, 1-diimidazole alkane, 4-dimethylamino pyridine or 1- (3-dimethylamino propyl) -3-ethyl carbodiimide hydrochloride;
the silica gel column eluent is a mixed solution of ethyl acetate and methanol, wherein the volume ratio of ethyl acetate to methanol is (10-50): 1.
3. The method for preparing chlorogenic acid derivative for clearing away heat and toxic material according to claim 2, comprising the following steps:
(1) under the protection of nitrogen, dissolving 20g of chlorogenic acid in tetrahydrofuran solution at room temperature, adding 9.1g of formic acid, raising the temperature to 100 ℃, stirring for reaction for 8 hours, detecting by TLC (thin layer chromatography), washing the filtrate with saturated saline solution and water for multiple times, extracting with ethyl acetate, combining organic layers, drying with anhydrous calcium chloride, dissolving the dried product in dichloromethane, adding dimethyl sulfate and sodium hydroxide, stirring for dissolution, raising the temperature to 60 ℃, refluxing for reaction for 7 hours, adding a large amount of ice water for quenching reaction, extracting with ethyl acetate, combining the organic layers, drying with anhydrous sodium sulfate, and carrying out reduced pressure distillation to obtain a compound A;
(2) dissolving 14g of the compound A in dichloromethane, adding 6.2g of 1- (2-aminoethyl) pyrrolidine, adding 1-hydroxybenzotriazole, heating to 60 ℃, carrying out reflux reaction for 3h, after TLC detection reaction is finished, adding saturated sodium carbonate to quench reaction, washing filtrate with hydrochloric acid solution, saturated saline solution and water, extracting with ethyl acetate, combining organic layers, concentrating under reduced pressure to obtain extract, carrying out elution chromatography on the extract through a silica gel column, collecting eluent which is a mixed solution of ethyl acetate and methanol in a volume ratio of 10:1, and concentrating the eluent under reduced pressure to obtain the target product.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724142A (en) * | 2021-01-19 | 2021-04-30 | 籍建亚 | Antidepressant theophylline derivative and preparation method thereof |
| CN112851576A (en) * | 2021-01-19 | 2021-05-28 | 谢天龙 | Chlorogenic acid derivative for clearing away heat and toxic materials and preparation method thereof |
| CN112876469A (en) * | 2021-01-19 | 2021-06-01 | 籍建亚 | Lupine derivative with effects of relieving cough and reducing phlegm and preparation method thereof |
| CN114773255A (en) * | 2022-05-24 | 2022-07-22 | 遵义医科大学 | Chlorogenic acid analogue and preparation method and application thereof |
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| CN112851576A (en) * | 2021-01-19 | 2021-05-28 | 谢天龙 | Chlorogenic acid derivative for clearing away heat and toxic materials and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724142A (en) * | 2021-01-19 | 2021-04-30 | 籍建亚 | Antidepressant theophylline derivative and preparation method thereof |
| CN112851576A (en) * | 2021-01-19 | 2021-05-28 | 谢天龙 | Chlorogenic acid derivative for clearing away heat and toxic materials and preparation method thereof |
| CN112876469A (en) * | 2021-01-19 | 2021-06-01 | 籍建亚 | Lupine derivative with effects of relieving cough and reducing phlegm and preparation method thereof |
| CN112876469B (en) * | 2021-01-19 | 2022-08-26 | 广东博卓医药科技有限公司 | Lupine derivative with effects of relieving cough and reducing phlegm and preparation method thereof |
| CN114773255A (en) * | 2022-05-24 | 2022-07-22 | 遵义医科大学 | Chlorogenic acid analogue and preparation method and application thereof |
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