CN111233810B - Preparation method and application of hydroxycinnamoyl ester type catechin - Google Patents
Preparation method and application of hydroxycinnamoyl ester type catechin Download PDFInfo
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Abstract
The invention relates to a preparation method and application of hydroxycinnamoyl ester type catechin. The hydroxycinnamoyl catechin includes 4 kinds of catechins named as epicatechin trans-coumarate, epicatechin trans-caffeate, epigallocatechin trans-coumarate and epigallocatechin trans-caffeate, respectively. The 4 hydroxycinnamoyl ester catechins are prepared by performing four steps of total acetylation, acetyl removal on phenolic hydroxyl, phenolic hydroxyl silanization and 3-bit acetyl removal on epicatechin and epigallocatechin, and then respectively performing esterification and protective group removal on the epicatechin and the epigallocatechin and acetyl chloride of acetylated caffeic acid or coumaric acid. The 4 hydroxycinnamoyl ester type catechins have certain inhibiting effect on alpha-glucosidase activity, can be used for hypoglycemic drugs, and have important significance in the fields of agriculture and medicine.
Description
Technical Field
The invention belongs to the technical field of natural medicinal chemistry, and particularly relates to a preparation method and application of four hydroxycinnamoyl ester type catechins named as epicatechin trans-coumarate, epicatechin trans-caffeate, epigallocatechin trans-coumarate and epigallocatechin trans-caffeate respectively.
Background
The tea leaves contain rich tea polyphenol which accounts for 18 to 36 percent of dry substances of the tea leaves. Wherein most of the catechin is catechin (flavanol) and accounts for 12% -24% of dry matter of tea. Researches show that catechin is an important flavor substance in tea. In addition, catechin also has antiinflammatory, antioxidant, anticancer, cardiovascular and neuroprotective effects.
Chemical synthesis experiments usually require special reaction conditions, and the pharmaceutical reagents used in the reactions are generally dangerous. The synthesis method of the catechin disclosed in the prior art is complex and harsh in reaction conditions, and the conditions of a common laboratory cannot meet the reaction requirements and cannot complete the preparation. How to screen the existing preparation method and reaction raw materials, and the design of the preparation method of the four hydroxycinnamoyl ester type catechins with simple method and mild conditions has important significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a preparation method of hydroxyl cinnamoyl ester catechin.
The invention also aims to provide the inhibition effect of the hydroxycinnamoyl ester type catechin prepared by the method on alpha-glucosidase, and the inhibition effect can be applied to the preparation of hypoglycemic drugs.
In order to solve the technical problem of the invention, the technical scheme is as follows:
a preparation method of hydroxycinnamoyl ester type catechin comprises 4 kinds of catechin, wherein the 4 kinds of catechin are epicatechin trans coumarate namely (-) -epicatechin 3-O-p-coumarate, epicatechin trans caffeate namely (-) -epicatechin 3-O-caffeate, epigallocatechin trans coumarate namely (-) -epigallocatechin 3-O-p-coumarate, epigallocatechin trans caffeate namely (-) -epigallocatechin 3-O-p-caffeate, and the structural formulas of the epigallocatechin trans caffeate are respectively shown as formula I, formula II, formula III and formula IV,
the preparation method of the hydroxycinnamoyl ester type catechin comprises the following steps:
s1, preparing 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin by taking Epicatechin (EC) as a raw material through four reactions of full acetylation, acetyl removal on phenolic hydroxyl, phenolic hydroxyl silanization and 3-acetyl removal;
using Epigallocatechin (EGC) as raw material, and making 5,7,3',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin through four reactions of full acetylation, removing acetyl on phenolic hydroxyl, silanization of phenolic hydroxyl and removing 3-acetyl;
s2, preparing 3',4' -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate;
weighing 92.0mg of 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin obtained in step S1 into a 25mL round-bottomed flask, adding 0.2mL of dried pyridine and 2.0mL of dried dichloromethane, slowly adding dropwise 3.0mL of dried dichloromethane containing 0.18mmol of 3,4-O-diacetyl caffeoyl chloride under ice bath conditions, reacting overnight at room temperature, adding an appropriate amount of water and an equal volume of dichloromethane for extraction three times, drying the dichloromethane layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography with petroleum ether: elution with ethyl acetate =30 gave 3",4" -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate;
s3, preparing 4' -O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-coumarate;
395.0mg of 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin obtained in step S1 was weighed into a 25mL round-bottomed flask, 1.5mL of dried pyridine and 3.0mL of dried dichloromethane were added, 5.0mL of dried dichloromethane containing 0.80mmol of 4-O-acetylated coumaroyl chloride was slowly added dropwise under ice bath conditions, the mixture was reacted overnight at room temperature, an appropriate amount of water and an equal volume of dichloromethane were added thereto to extract three times, the dichloromethane layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting product was subjected to silica gel column chromatography to obtain a silica gel column containing petroleum ether: elution with ethyl acetate =50 gave 4 "-O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans coumarate;
s4, preparing 3',4' -O-diacetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-caffeate;
weighing 500.0mg of 5,7,3',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin prepared in step S1 into a 100mL round-bottom flask, adding 2.0mL of dried pyridine and 5.0mL of dried dichloromethane, slowly adding 8.0mL of dried dichloromethane containing 1.9mmol of 3,4-O-diacetyl caffeoyl chloride dropwise under ice bath conditions, reacting overnight at room temperature, adding an appropriate amount of water and dichloromethane with the same volume, extracting three times, drying the dichloromethane layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography with petroleum ether: elution with ethyl acetate =30 gave 3",4" -O-diacetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-caffeate;
s5, preparing 4 '-O-acetyl-5,7,3', 4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin trans-coumarate;
weighing 370.0mg of 5,7,3',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin prepared in step S1 into a 100mL round-bottomed flask, adding 2.0mL of dried pyridine and 5.0mL of dried dichloromethane, slowly adding 7.0mL of dried dichloromethane containing 1.5mmol of 4-O-acetylated coumaroyl chloride dropwise under ice bath conditions, reacting overnight at room temperature, adding an appropriate amount of water and dichloromethane of the same volume for extraction three times, drying the dichloromethane layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography with petroleum ether: ethyl acetate =50 to give 4 "-O-acetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-coumarate after elution;
s6, preparing epicatechin trans-caffeate;
weighing 164.0mg of the 3',4' -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate prepared in the step S2 into a 25mL round-bottom flask, adding 28.0mg of potassium bifluoride and 6.0mL of dried methanol, reacting for 6 hours at 50 ℃, and carrying out LH-20 gel column chromatography on a reaction product to elute the product by the methanol to obtain the epicatechin trans-caffeate;
s7, preparing epigallocatechin trans-caffeate;
weighing 60.0mg of 3 '-O-diacetyl-5,7,3', 4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-caffeate prepared in the step S4 into a 25mL round-bottom flask, adding 200.0mg of potassium bifluoride, adding 5.0mL of dry methanol, reacting at 50 ℃ for 6 hours, carrying out LH-20 gel column chromatography on a reaction product, and eluting with methanol to obtain epigallocatechin trans-caffeate;
s8, preparing epicatechin trans-coumarate;
163.0mg of 4' -O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans coumarate prepared in step S3 was weighed into a 25mL round bottom flask, 136.0mg of potassium fluorohydride was added, 6.0mL of dried methanol was added, the reaction was carried out at room temperature for 3.5 hours, an appropriate amount of water was added after the reaction was completed, extraction was carried out three times with ethyl acetate of the same volume, the ethyl acetate layer was dried with anhydrous sodium sulfate and then concentrated, and the mixture was subjected to silica gel column chromatography with petroleum ether: ethyl acetate =1:1 to give 4 "-O-acetyl-epicatechin trans coumarate after elution;
weighing 50.0mg of 4' -O-acetyl-epicatechin trans-coumarate in a 10mL round-bottom flask, adding 450.0mg of ammonium acetate, adding 2.0mL of 80% methanol water solution by volume fraction, reacting at room temperature for 5.5 hours, performing LH-20 gel column chromatography on a reaction product, and eluting with methanol to obtain epicatechin trans-coumarate;
s9, preparing epigallocatechin trans-coumarate;
weighing 130.0mg of the 4' -O-acetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-coumarate prepared in the step S5 into a 25mL round-bottom flask, adding 476.0mg of potassium bifluoride, adding 8.0mL of dry methanol, reacting at 50 ℃ for 6 hours, concentrating a reaction product, performing LH-20 gel column chromatography, and eluting with methanol to obtain 4' -O-acetyl-epigallocatechin trans-coumarate;
weighing 36.0mg of 4' -O-acetyl-epigallocatechin trans-coumarate in a 10mL round-bottom flask, adding 460.0mg of ammonium acetate, adding 2.0mL of 80% methanol aqueous solution by volume fraction, reacting at room temperature for 5 hours, carrying out LH-20 gel column chromatography on a reaction product, and eluting with methanol to obtain epigallocatechin trans-coumarate;
wherein, the steps S2, S3, S4 and S5 are not in sequence, and the steps S6, S7, S8 and S9 are not in sequence.
As a further improvement of the preparation method of the hydroxycinnamoyl ester type catechin,
preferably, 3,4-O-diacetyl caffeoyl chloride, as described in step S2, is prepared by:
180.1mg caffeic acid was weighed into a 25mL round bottom flask, 0.3mL dry pyridine, 0.5mL acetic anhydride was added and stirred overnight at room temperature under dry tube protection. After the reaction is finished, adding water to stop the reaction, and rotationally evaporating to dryness to obtain acetylated caffeic acid, namely 3,4-O-diacetyl caffeic acid; transferring the acetylated caffeic acid after reaction to a 50mL round-bottom flask, adding 10mL thionyl chloride, heating and refluxing at 90 ℃ for 3 hours to obtain crude 3,4-O-diacetyl caffeoyl chloride, and storing for later use.
Preferably, the 4-O-acetylated coumaroyl chloride described in step S3 is prepared by:
656.0mg coumaric acid was weighed into a 25mL round bottom flask, 0.8mL dry pyridine, 1.0mL acetic anhydride was added and stirred overnight at room temperature under dry tube protection. After the reaction is finished, adding water to stop the reaction, and obtaining acetylated coumaric acid after rotary evaporation to dryness; transferring the acetylated coumaric acid after reaction into a 25mL round-bottom flask, adding 3.0mL thionyl chloride, heating and refluxing at 90 ℃ for 3 hours to obtain a crude product of 4-O-acetylated coumaric acid chloride, and storing for later use.
In order to solve another technical problem, the invention provides another technical scheme that the hydroxycinnamoyl ester type catechin prepared by the preparation method is used for preparing the hypoglycemic medicament.
The application of the hydroxycinnamoyl ester type catechin in preparing the hypoglycemic medicament is further improved, the hypoglycemic medicament comprises an oral administration type and an injection type, the oral administration type comprises tablets, capsules, granules and dropping pills, and the injection type comprises injection and mixed rotary fluid.
Compared with the prior art, the invention has the beneficial effects that:
1) The invention provides a synthesis method of four hydroxycinnamoyl ester type catechins, which is different from the synthesis method in the prior art, the hydroxyl protecting groups, the esterification reaction conditions, the hydrolysis conditions of the protecting groups and the like adopted by the synthesis experiment have obvious advantages, the preparation method is simple, the conditions are mild, the implementation is easy, the cost is lower, and the invention has very good application prospect
2) The four hydroxycinnamoyl ester type catechins prepared by the invention have medical activity, have certain inhibition effect on alpha-glucosidase activity, can be used for preparing oral and injection type hypoglycemic drugs, and have important significance in the fields of agriculture and medicine.
Drawings
FIG. 1 shows the synthesis route of four hydroxycinnamoyl type catechins;
the designations in the drawings have the following meanings:
1a, 3,5,7,3',4' -O-pentaacetyl-epicatechin
1b, 3,5,7,3',4',5' -O-hexaacetyl-epigallocatechin
2a, 3-O-acetyl-epicatechin
2b, 3-O-acetyl-epigallocatechin
3a, 3-O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin
3b, 3-O-acetyl-5,7,3 ',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin
4a, 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin
4b, 5,7,3',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin
5a, 3,4-O-diacetyl caffeoyl chloride
5b, 4-O-acetylated coumaroyl chloride
6a, 3',4' -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate
6b, 4 "-O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans coumarate
6c, 3',4' -O-diacetyl-5,7,3 ',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin trans-caffeate
6d, 4 '-O-acetyl-5,7,3', 4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin trans-coumarate
7a, 4 "-O-acetyl-epicatechin trans-coumarate
7b, 4 "-O-acetyl-epigallocatechin trans-coumarate
8a, epicatechin trans-caffeate
8b epicatechin trans coumarate
8c Epigallocatechin Trans-caffeate
8d Epigallocatechin Trans coumarate
Detailed Description
The invention is further described below with reference to the following examples:
this section generally describes the materials used in the experiments of the present invention, as well as the experimental methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is described herein in detail as much as possible. It will be apparent to those skilled in the art that the materials, equipment, and methods of operation used in the present invention are well known in the art to which the invention pertains, unless otherwise specified.
Example 1
Preparing hydroxycinnamoyl catechin of epicatechin trans-coumarate, epicatechin trans-caffeate, epigallocatechin trans-coumarate and epigallocatechin trans-caffeate;
1.1 instruments and reagents
1 H nuclear magnetic resonance spectrum adopts Agilent DD2600 MHz nuclear magnetic resonanceMeasuring; the mass spectrum was obtained by Agilent6465UPLC-Q-TOF-MS.
Epicatechin (EC) and Epigallocatechin (EGC) were purchased from Chengdu biopharmaceutical corporation and Hubei Jusheng technology corporation, respectively; caffeic acid and p-coumaric acid are purchased from An Naiji chemical; other reagents are all domestic analytical purifiers.
1.2 the synthetic route of hydroxycinnamic ester type catechin of epicatechin trans-coumarate, epicatechin trans-caffeate, epigallocatechin trans-coumarate and epicatechin trans-caffeate is shown in figure 1;
1.3 the specific implementation method comprises the following steps:
synthesis of compound 1 a:
1.16g (4.0 mmol) of Epicatechin (EC) was weighed into a 50mL round bottom flask, 6.0mL of dried pyridine and 8.0mL of acetic anhydride (84.6 mmol) were added, and the mixture was stirred at room temperature overnight under protection of a dry tube. After the reaction is finished, water is added to stop the reaction, and the EC fully acetylated product 3,5,7,3',4' -O-pentaacetyl-epicatechin (1a, 1.9g, white powder, yield 95%) can be obtained after rotary evaporation to dryness. 1 H NMR(600MHz,CDCl 3 ):7.33(1H,s),7.25(1H,d,J＝8.4Hz),7.18(1H,d,J＝8.4Hz),6.65(1H,br s),6.55(1H,br s),5.37(1H,br s),5.09(1H,s),2.95(1H,dd,J＝18.0,4.2Hz),2.87(1H,br d,J＝18.0Hz),2.27(9H,s),2.26(3H,s),1.90(3H,s)。
Synthesis of compound 1 b:
1.2g (3.9 mmol) of Epigallocatechin (EGC) was weighed into a 50mL round-bottomed flask, 6.0mL of dried pyridine and 10.0mL of acetic anhydride (105.7 mmol) were added, and the mixture was stirred at room temperature overnight under protection of a drying tube. After the reaction is finished, adding water to stop the reaction, and rotationally evaporating to dryness to obtain an EGC (epigallocatechin gallate) full acetylation product: 3,5,7,3',4',5' -O-hexaacetyl-epigallocatechin (1b, 2.1g, white powder, yield 94%). 1 H NMR(600MHz,CDCl 3 ):7.20(2H,s),6.65(1H,br s),6.55(1H,br s),5.36(1H,br s),5.07(1H,s),2.94(1H,dd,J＝18.0,4.2Hz),2.88(1H,br d,J＝17.4Hz),2.25-2.28(15H,m),1.92(3H,s)。
Synthesis of compound 2 a:
500.0mg (1.0 mmol) of compound 1a are weighed out at 100mA round-bottomed flask was charged with 50mL of an 80% aqueous methanol solution, 7.8g (101.2 mmol) of ammonium acetate, and the mixture was stirred at room temperature overnight. After the reaction is finished, adding a proper amount of water, removing methanol through rotary concentration, extracting for three times by using ethyl acetate with the same volume, concentrating an ethyl acetate layer, and performing silica gel column chromatography to obtain a product with ethyl acetate: methanol =20 was eluted at the rate of 1 to obtain 3-O-acetyl-epicatechin (2a, 259.0mg, white powder, yield 78%). 1 H NMR(600MHz,DMSO-d 6 ):9.29(1H,s),9.02(1H,s),8.92(1H,s),8.83(1H,s),6.83(1H,s),6.69(1H,d,J＝8.4Hz),6.65(1H,d,J＝7.8Hz),5.93(1H,s),5.76(1H,s),5.23(1H,br s),4.93(1H,s),2.87(1H,dd,J＝17.4,4.2Hz),2.58(1H,br d,J＝16.8Hz),1.87(3H,s)。
Synthesis of compound 2 b:
in a 500mL round-bottom flask, 4.2g (1.0 mol) of Compound 1b was weighed, and 80mL of 80% aqueous methanol solution and 1.0g (11.9 mmol) of sodium hydrogencarbonate were added and the mixture was stirred at room temperature overnight. After the reaction is finished, adding a proper amount of water, extracting for three times by using ethyl acetate with the same volume, concentrating an ethyl acetate layer, and performing silica gel column chromatography by using ethyl acetate: methanol =1:1 eluted to give the compound 3-O-acetyl-epigallocatechin (2b, 1.05mg, white powder, yield 40%). 1 H NMR(600MHz,DMSO-d 6 ):9.25(1H,s),8.99(1H,s),8.78(1H,s),7.99(1H,s),6.35(2H,s),5.92(1H,d,J＝1.2Hz),5.75(1H,d,J＝1.8Hz),5.21(1H,br s),4.85(1H,s),2.87(1H,dd,J＝17.4,4.8Hz),2.57(1H,br d,J＝16.8Hz),1.88(3H,s)。
Synthesis of compound 3 a:
200.0mg (0.6 mmol) of Compound 2a was weighed into a 100mL round-bottomed flask, and 10mL of a dried dichloromethane solution containing 723.4mg (4.8 mmol) of t-butyldimethylchlorosilane was slowly added dropwise under ice-bath conditions to 10mL of dry dichloromethane, 816.0mg (12.0 mmol) of imidazole, 40mg (0.33 mmol) of 4-dimethylaminopyridine. Stir at room temperature overnight. After the reaction is finished, adding a proper amount of water, extracting with dichloromethane with the same volume for three times, washing a dichloromethane layer solution with saturated sodium chloride, concentrating, and performing silica gel column chromatography with petroleum ether: ethyl acetate =100 to give the compound 3-O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl after elutionEpicatechin (3a, 450.0mg, clear oil, yield 95%). 1 H NMR(600MHz,CDCl 3 ):6.87(1H,s),6.85(1H,d,J＝8.4Hz),6.79(1H,d,J＝7.8Hz),6.13(1H,br s),5.96(1H,br s),5.37(1H,br s),4.94(1H,s),2.90(1H,dd,J＝17.4,4.2Hz),2.83(1H,br d,J＝18.0Hz),1.87(3H,s),0.94-0.98(36H,m),0.15-0.21(24H,m)。
Synthesis of compound 3 b:
500.0mg (1.4 mmol) of Compound 2b was weighed into a 100mL round-bottomed flask, and 10mL of a dried dichloromethane solution containing 2.4g (16.0 mmol) of t-butyldimethylchlorosilane was slowly added dropwise under ice-bath conditions to the flask in which were added 10mL of dried dichloromethane, 2.4g (35.3 mmol) of imidazole and 100mg (0.82 mmol) of 4-dimethylaminopyridine. Stir at room temperature overnight. After the reaction is finished, adding a proper amount of water, extracting with dichloromethane with the same volume for three times, washing a dichloromethane layer solution with saturated sodium chloride, concentrating, and performing silica gel column chromatography with petroleum ether: ethyl acetate =200, 1 was eluted to give the compound 3-O-acetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin (3b, 970.0mg, clear oil, yield 74%). 1 H NMR(600MHz,CDCl 3 ):6.55(2H,s),6.11(1H,d,J＝2.4Hz),5.95(1H,d,J＝2.4Hz),5.36(1H,m),4.91(1H,br s),2.89(1H,dd,J＝17.4,4.8Hz),2.81(1H,dd,J＝17.4,3.0Hz),1.86(3H,s),0.90-0.97(45H,m),0.08-0.21(30H,m)。
Synthesis of compound 4 a:
100.0mg (0.13 mmol) of Compound 3a was weighed out and dissolved in 100. Mu.L of dry dichloromethane in a 50mL round-bottomed flask, and then dried methanol (10mL) and 50.0mg (0.36 mmol) of potassium carbonate were added, followed by stirring at room temperature for 2 hours. After the reaction is finished, adding a proper amount of water, extracting three times by using equal volume of ethyl acetate, drying and concentrating ethyl acetate layer solution by using anhydrous sodium sulfate, and performing silica gel column chromatography by using petroleum ether: ethyl acetate =100 to give compound 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin (4a, 38.0mg, clear oil, yield 40%). 1 H NMR(600MHz,CDCl 3 ):6.94(1H,d,J＝1.8Hz),6.92(1H,dd,J＝8.4,1.8Hz),6.84(1H,d,J＝7.8Hz),6.11(1H,d,J＝2.4Hz),5.96(1H,d,J＝1.8Hz),4.86(1H,s),4.20(1H,br s),2.86(1H,s),2.85(1H,s),0.99(9H,s),0.97(9H,s),0.96(9H,s),0.95(9H,s),0.16-0.22(24H,m)。
Synthesis of compound 4 b:
970.0mg (1.06 mmol) of compound 3b was weighed into a 100mL round-bottom flask, dissolved in 100uL of dry dichloromethane, and then added with dry methanol 40mL,200mg (1.44 mmol) of potassium carbonate and stirred at room temperature for 2 hours. After the reaction is finished, adding a proper amount of water, extracting for three times by using ethyl acetate with the same volume, drying and concentrating ethyl acetate layer solution by using anhydrous sodium sulfate, and performing silica gel column chromatography by using petroleum ether: ethyl acetate =200 to give compound 5,7,3',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin (4b, 353.0mg, clear oil, yield 38%). 1 H NMR(600MHz,CDCl 3 ):6.59(2H,s),6.09(1H,d,J＝1.8Hz),5.95(1H,d,J＝2.4Hz),4.82(1H,br s),4.16(1H,m),3.47(1H,s),2.85(1H,dd,J＝16.8,4.2Hz),2.80(1H,dd,J＝16.8,3.0Hz),0.90-0.99(45H,m),0.10-0.22(30H,m)。
Synthesis of compound 5 a:
180.1mg (1.0 mmol) of caffeic acid was weighed into a 25mL round bottom flask, 0.3mL of dried pyridine, 0.5mL of acetic anhydride (5.3 mmol) were added, and the mixture was stirred overnight at room temperature under the protection of a drying tube. After the reaction is finished, water is added to stop the reaction, and the acetylated caffeic acid (3,4-O-diacetyl caffeic acid, 250.8mg, yield 95%) can be obtained after rotary evaporation to dryness. 1 H NMR(600MHz,DMSO-d 6 ) 12.47 (1h, s) 7.66 (1h, s), 7.63 (1h, d, j =8.4 hz), 7.57 (1h, d, j =16.2 hz), 7.31 (1h, d, j =8.4 hz), 6.53 (1h, d, j =16.2 hz), 2.29 (3h, s). Transferring the acetylated caffeic acid after reaction to a 50mL round-bottom flask, adding 10mL thionyl chloride, heating and refluxing for 3 hours at 90 ℃ to obtain a crude compound 3,4-O-diacetyl caffeoyl chloride (5 a), and directly using the crude compound in the next reaction.
Synthesis of compound 5 b:
656.0mg (4.0 mmol) caffeic acid was weighed into a 25mL round bottom flask, 0.8mL dry pyridine, 1.0mL acetic anhydride (10.6 mmol) was added, and stirred under dry tube overnight at room temperature. After the reaction is finished, adding water to stop the reaction, and obtaining acetylated coumaric acid (4-O-acetylation) after rotary evaporation to drynessCoumaric acid, 774.6mg, 94% yield). 1 H NMR(600MHz,DMSO-d 6 ) 12.36 (1H, s) 7.73 (2H, d, J = 9.0Hz), 7.60 (1H, d, J = 14.4Hz), 7.18 (2H, d, J = 8.4Hz), 6.50 (1H, d, J = 16.2Hz), 2.28 (3H, s). The acetylated coumaric acid (251.0 mg, 1.2mmol) after the reaction was transferred to a 25mL round-bottom flask, 3.0mL thionyl chloride was added, and the mixture was heated under reflux at 90 ℃ for 3 hours to obtain a crude compound, 4-O-acetylated coumaroyl chloride (5 b), which was used directly in the next reaction.
Synthesis of compound 6 a:
Synthesis of compound 6 b:
Synthesis of compound 6 c:
Synthesis of compound 6 d:
6a (164.0 mg,0.16 mmol) was weighed into a 25mL round-bottomed flask, potassium bifluoride (28.0 mg, 1.64mmol) was added, 6.0mL of dried methanol was further added, and the reaction was carried out at 50 ℃ for 6 hours. The reaction product was subjected to LH-20 gel column chromatography and eluted with methanol to give the compound epicatechin trans-caffeate (8a, 52.0mg, white powder, yield 70%). 1 H NMR(600MHz,DMSO-d 6 ) 7.32 (1H, d, J = 16.2Hz), 6.98 (1H, s), 6.95 (1H, dd, J =6.6, 1.8Hz), 6.88 (1H, s), 6.73 (1H, d, J = 7.8Hz), 6.70 (1H, dd, J =8.4, 1.2Hz), 6.67 (1H, dd, J = 7.8Hz), 6.12 (1H, d, J =15.6 Hz), 5.94 (1H, d, J = 1.8Hz), 5.81 (1H, d, J = 1.8Hz), 5.31 (1H, br s), 5.01 (1H, s), 2.92 (1H, dd, J =17.4, 4.8Hz), 2.67 (1H, 16J). HR-ESI-MS (negative ion) M/z451.1040[ M-H] - 。
Synthesis of compound 8 b:
7a (50.0mg, 0.1mmol) was weighed in a 10mL round-bottomed flask, and ammonium acetate (450.0mg, 5.8mmol) was added thereto, and 2.0mL of an 80% aqueous methanol solution was added thereto, followed by reaction at room temperature for 5.5 hours. The reaction product was subjected to LH-20 gel column chromatography and eluted with methanol to give the compound epicatechin trans coumarate (8b, 45.6mg, white powder, yield 88%). 1H NMR (600MHz, DMSO-d 6 ) 7.50 (2H, d, J =8.4 Hz), 7.41 (1H, d, J =15.6 Hz), 6.88 (1H, d, J =1.8 Hz), 6.75 (2H, d, J =9.0 Hz), 6.70 (1H, dd, J =8.4,1.2 Hz), 6.67 (1H, d, J =7.8 Hz), 6.24 (1H, d, J =15.6 Hz), 5.93 (1H, d, J =1.8 Hz), 5.80 (1H, d, J =1.8 Hz), 5.32 (1H, br s), 5.01 (1H, s), 2.92 (1H, dd, J17.4, 4.8 Hz), 2.66 (1H, br d, 16.2 Hz). HR-ESI-MS (negative ion) M/z435.1088[ M-H] - 。
Synthesis of compound 8 c:
6c (60.0 mg, 0.05mmol) was weighed in a 25mL round-bottomed flask, potassium bifluoride (200.0 mg, 2.56mmol) was added thereto, 5.0mL of dried methanol was added thereto, and the reaction was carried out at 50 ℃ for 6 hours. The reaction product was subjected to LH-20 gel column chromatography and eluted with methanol to give the compound epigallocatechin trans-caffeate (8c, 15.0mg, white powder, yield 60%). 1 H NMR(600MHz,DMSO-d 6 ):7.33(1H,d,J＝16.8Hz),6.98(1H,d,J＝1.8Hz),6.96(1H,dd,J＝8.4,1.8Hz),6.72(1H,d,J＝8.4Hz),6.39(2H,s),6.09(1H,d,J＝16.2Hz),5.93(1H,d,J＝1.8Hz),5.79(1H,dJ =2.4 Hz), 5.28 (1h, br s), 4.93 (1h, s), 2.90 (1h, dd, J =17.4,4.8 Hz), 2.64 (1h, br d, J = 16.2hz). HR-ESI-MS (negative ion) m/z 451.1033[ M-H ]] - 。
Synthesis of compound 8 d:
in a 10mL round-bottomed flask, 7b (36.0 mg, 0.07mmol) was weighed, ammonium acetate (460.0 mg,6.0 mmol) was added, and 2.0mL of an 80% aqueous methanol solution was added to the flask, and the mixture was reacted at room temperature for 5 hours. The reaction product was subjected to LH-20 gel column chromatography and eluted with methanol to give epigallocatechin trans-coumarate (8d, 18.1mg, white powder, yield 55%). 1 H NMR(600MHz,DMSO-d 6 ) 7.49 (2h, d, j =8.4 hz), 7.41 (1h, d, j =15.6 hz), 6.75 (2h, d, j =8.4 hz), 6.39 (2h, s), 6.22 (1h, d, j =15.6 hz), 5.93 (1h, d, j =2.4 hz), 5.79 (1h, d, j =1.8 hz), 5.30 (1h, br s), 4.93 (1h, s), 2.91 (1h, dd, j =17.4,4.8 hz), 2.65 (1h, br d, j = 16.2hz). HR-ESI-MS (negative ion) M/z467.0979[ M-H] - 。
Example 2
Four hydroxycinnamoyl-type catechins, epicatechin trans-coumarate, epigallocatechin trans-coumarate and epigallocatechin trans-caffeate, prepared in example 1 were subjected to an in vitro inhibition experiment of α -glucosidase activity.
2.1 Experimental materials and reagents
Acarbose, potassium phosphate buffer (PPBS, 10mM, pH 6.9), alpha-glucosidase (0.1U. ML) -1 ) 4-Nitrophenyl-alpha-D-glucopyranoside (pNPG, 2.5 mM), dimethyl sulfoxide (DMSO)
2.2 Experimental methods and results
Adding 60 mu L of alpha-glucosidase solution into a 96-well plate, respectively adding 60 mu L of four hydroxycinnamoyl ester type catechins with different concentration gradients, pre-incubating for 10min at 37 ℃, respectively adding 60 mu L of pNPG solution, continuously incubating for 20min at 37 ℃, placing in an enzyme labeling instrument (25 ℃), and recording the A value of the reaction solution under visible light with the wavelength of 405 nm. All samples were replicated 3 times and recorded as a sample. 60 μ L of PPBS was used instead of α -glucosidase and recorded as A blank (repeated 3 times) and zeroed. The sample solution was replaced with 60. Mu.L of PPBS and recorded as the A test. The sample solution and α -glucosidase were replaced with 120 μ L of PPBS, denoted as A control (3 replicates).
The enzyme inhibition ratio of acetylcholinesterase was calculated according to the following formula:
inhibition (%) = (1- (a sample-a blank)/(a test-a control)) × 100%.
The relative activity of the enzyme is plotted against the concentration of the inhibitor, and the IC of the action of the four hydroxycinnamoyl ester catechins and the alpha-glucosidase can be calculated according to the inhibition curve 50 The value is obtained. The results obtained are shown in the following table:
note: positive control drug acarbose
As can be seen from the results in the table, four hydroxycinnamoyl ester-type catechins prepared by the present invention: the epicatechin trans-coumarate, epicatechin trans-caffeate, epigallocatechin trans-coumarate and epigallocatechin trans-caffeate have strong inhibition effects on alpha-glucosidase, can be applied to preparation of hypoglycemic drugs, and have wide application prospects.
It should be understood that the examples and embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the present disclosure, and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this disclosure.
Claims (3)
1. A method for preparing hydroxycinnamoyl ester type catechin comprises 4 kinds of catechin, wherein the 4 kinds of catechin are respectively epicatechin trans coumarate ((-) -epicatechin 3-O-p-coumarate), epicatechin trans caffeate ((-) -epicatechin 3-O-caffeate), and epigallocatechin trans coumarate ((-) -epigallocatechin)
3-O-p-coumaroate, epigallocatechin trans-caffeate (-) -epigallocatechin
The structural formula of the 3-O-caffeoate is respectively shown as formula I, formula II, formula III and formula IV,
the preparation method of the hydroxycinnamoyl ester type catechin is characterized by comprising the following steps:
s1, preparing 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin by taking Epicatechin (EC) as a raw material through four reactions of full acetylation, acetyl removal on phenolic hydroxyl, phenolic hydroxyl silanization and 3-acetyl removal;
using Epigallocatechin (EGC) as raw material, and making 5,7,3',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin through four reactions of full acetylation, removing acetyl on phenolic hydroxyl, silanization of phenolic hydroxyl and removing 3-acetyl;
s2, preparing 3',4' -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate;
weighing 92.0mg of 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin obtained in step S1 into a 25mL round-bottomed flask, adding 0.2mL of dried pyridine and 2.0mL of dried dichloromethane, slowly adding dropwise 3.0mL of dried dichloromethane containing 0.18mmol of 3,4-O-diacetyl caffeoyl chloride under ice bath conditions, reacting overnight at room temperature, adding an appropriate amount of water and an equal volume of dichloromethane for extraction three times, drying the dichloromethane layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography with petroleum ether: elution with ethyl acetate =30 gave 3",4" -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate;
s3, preparing 4' -O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-coumarate;
395.0mg of 5,7,3',4' -O-tetra-tert-butyldimethylsilyl-epicatechin obtained in step S1 was weighed into a 25mL round-bottomed flask, 1.5mL of dried pyridine and 3.0mL of dried dichloromethane were added, 5.0mL of dried dichloromethane containing 0.80mmol of 4-O-acetylated coumaroyl chloride was slowly added dropwise under ice bath conditions, the mixture was reacted overnight at room temperature, an appropriate amount of water and an equal volume of dichloromethane were added thereto to extract three times, the dichloromethane layer was dried over anhydrous sodium sulfate and then concentrated, and the resulting product was subjected to silica gel column chromatography to obtain a silica gel column containing petroleum ether: elution with ethyl acetate =50 gave 4 "-O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans coumarate;
s4, preparing 3',4' -O-diacetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-caffeate;
weighing 500.0mg of 5,7,3',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin prepared in step S1 into a 100mL round-bottom flask, adding 2.0mL of dried pyridine and 5.0mL of dried dichloromethane, slowly adding 8.0mL of dried dichloromethane containing 1.9mmol of 3,4-O-diacetyl caffeoyl chloride dropwise under ice bath conditions, reacting overnight at room temperature, adding an appropriate amount of water and dichloromethane with the same volume, extracting three times, drying the dichloromethane layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography with petroleum ether: elution with ethyl acetate =30 gave 3",4" -O-diacetyl-5,7,3 ',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-caffeate;
s5, preparing 4 '-O-acetyl-5,7,3', 4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin trans-coumarate;
weighing 370.0mg of 5,7,3',4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin prepared in step S1 into a 100mL round-bottomed flask, adding 2.0mL of dried pyridine and 5.0mL of dried dichloromethane, slowly adding 7.0mL of dried dichloromethane containing 1.5mmol of 4-O-acetylated coumaroyl chloride dropwise under ice bath conditions, reacting overnight at room temperature, adding an appropriate amount of water and dichloromethane of the same volume for extraction three times, drying the dichloromethane layer with anhydrous sodium sulfate, concentrating, and performing silica gel column chromatography with petroleum ether: eluting with ethyl acetate =50 to obtain 4 ″ -O-acetyl-5,7,3 ',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin trans-coumarate;
s6, preparing epicatechin trans-caffeate;
weighing 164.0mg of the 3',4' -O-diacetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans-caffeate prepared in the step S2 into a 25mL round-bottom flask, adding 28.0mg of potassium bifluoride and 6.0mL of dried methanol, reacting for 6 hours at 50 ℃, and carrying out LH-20 gel column chromatography on a reaction product to elute the product by the methanol to obtain the epicatechin trans-caffeate;
s7, preparing epigallocatechin trans-caffeate;
weighing 60.0mg of 3 '-O-diacetyl-5,7,3', 4',5' -O-pentatert-butyldimethylsilyl-epigallocatechin trans-caffeate prepared in the step S4 into a 25mL round-bottom flask, adding 200.0mg of potassium bifluoride, adding 5.0mL of dry methanol, reacting at 50 ℃ for 6 hours, carrying out LH-20 gel column chromatography on a reaction product, and eluting with methanol to obtain epigallocatechin trans-caffeate;
s8, preparing epicatechin trans-coumarate;
163.0mg of 4' -O-acetyl-5,7,3 ',4' -O-tetra-tert-butyldimethylsilyl-epicatechin trans coumarate prepared in step S3 was weighed into a 25mL round bottom flask, 136.0mg of potassium bifluoride was added, 6.0mL of dried methanol was added, reaction was carried out at room temperature for 3.5 hours, an appropriate amount of water was added after the reaction was completed, extraction was carried out three times with ethyl acetate of equal volume, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated, and then subjected to silica gel column chromatography with petroleum ether: ethyl acetate =1:1 to give 4 "-O-acetyl-epicatechin trans coumarate after elution;
weighing 50.0mg of 4' -O-acetyl-epicatechin trans-coumarate in a 10mL round-bottom flask, adding 450.0mg of ammonium acetate, adding 2.0mL of 80% methanol aqueous solution by volume fraction, reacting at room temperature for 5.5 hours, performing LH-20 gel column chromatography on a reaction product, and eluting with methanol to obtain epicatechin trans-coumarate;
s9, preparing epigallocatechin trans-coumarate;
weighing 130.0mg of the 4' -O-acetyl-5,7,3 ',4',5' -O-penta-tert-butyldimethylsilyl-epigallocatechin trans-coumarate prepared in the step S5 into a 25mL round-bottom flask, adding 476.0mg potassium bifluoride, adding 8.0mL of dry methanol, reacting at 50 ℃ for 6 hours, concentrating a reaction product, performing LH-20 gel column chromatography, and eluting with methanol to obtain 4' -O-acetyl-epigallocatechin trans-coumarate;
weighing 36.0mg of 4' -O-acetyl-epigallocatechin trans-coumarate in a 10mL round-bottom flask, adding 460.0mg of ammonium acetate, adding 2.0mL of 80% methanol aqueous solution by volume fraction, reacting at room temperature for 5 hours, carrying out LH-20 gel column chromatography on a reaction product, and eluting with methanol to obtain epigallocatechin trans-coumarate;
wherein, the steps S2, S3, S4 and S5 are not in sequence, and the steps S6, S7, S8 and S9 are not in sequence.
2. The method for preparing hydroxycinnamoyl ester type catechins of claim 1, wherein 3,4-O-diacetyl caffeoyl chloride in step S2 is prepared by:
weighing 180.1mg of caffeic acid in a 25mL round-bottom flask, adding 0.3mL of dry pyridine and 0.5mL of acetic anhydride, stirring overnight at room temperature under the protection of a drying tube, adding water to stop the reaction, and evaporating to dryness in a rotating manner to obtain acetylated caffeic acid, namely 3,4-O-diacetyl caffeic acid; transferring the acetylated caffeic acid after reaction to a 50mL round-bottom flask, adding 10mL thionyl chloride, heating and refluxing at 90 ℃ for 3 hours to obtain 3,4-O-diacetyl caffeoyl chloride, and storing for later use.
3. The method for preparing hydroxycinnamoyl ester type catechins according to claim 1, wherein the 4-O-acetylated coumaroyl chloride in the step S3 is prepared by:
weighing 656.0mg coumaric acid in a 25mL round bottom flask, adding 0.8mL dry pyridine and 1.0mL acetic anhydride, stirring overnight at room temperature under the protection of a drying tube, adding water to stop the reaction, and performing rotary evaporation to dryness to obtain acetylated coumaric acid; transferring the acetylated coumaric acid after reaction into a 25mL round-bottom flask, adding 3.0mL thionyl chloride, heating and refluxing at 90 ℃ for 3 hours to obtain 4-O-acetylated coumaric acid chloride, and storing for later use.
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