CN111423407B - Caffeoylquinic acid derivative and preparation method and application thereof - Google Patents

Caffeoylquinic acid derivative and preparation method and application thereof Download PDF

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CN111423407B
CN111423407B CN201910022953.0A CN201910022953A CN111423407B CN 111423407 B CN111423407 B CN 111423407B CN 201910022953 A CN201910022953 A CN 201910022953A CN 111423407 B CN111423407 B CN 111423407B
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caffeoylquinic acid
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田瑜
许旭东
郭鹏
吴崇明
尚海
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Abstract

The invention discloses a caffeoylquinic acid derivative, a preparation method and application thereof, and the caffeoylquinic acid derivative has a structure shown in a general formula (I). The invention takes 3-O-caffeoylquinic acid as a raw material, reserves the structural skeleton of the 3-O-caffeoylquinic acid, introduces different amino substituent groups on 1-carboxyl, and substitutes or exposes 4-hydroxyl and 5-hydroxyl by ketal, thereby synthesizing the novel caffeoylquinic acid derivative with lipid-lowering activity. Compared with 3-O-caffeoylquinic acid, the caffeoylquinic acid derivative provided by the invention has better lipid-lowering activity.
Figure DDA0001941435280000011

Description

Caffeoylquinic acid derivative and preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry and therapeutics, in particular to a caffeoylquinic acid derivative, a preparation method and application thereof.
Background
Hyperlipidemia (HLP) can induce clinical common cardiovascular and cerebrovascular diseases, and is one of potential factors threatening human health. At present, the number of dyslipidemia patients in China is 2.0 hundred million, the incidence rate of normal people is 35-40%, and the number of middle-aged and elderly people is more than 60%. With the change of dietary structure and life style of people, the incidence rate of hyperlipidemia rises year by year, and the incidence age declines year by year, becoming a common disease and a frequently encountered disease in the current society. The prevention and treatment of the disease are hot spots and difficulties in the current medicine, and the use of lipid-lowering medicines is an effective treatment measure.
Currently, the common lipid-lowering drugs in clinic mainly include statin lipid-regulating drugs (atorvastatin and lovastatin), fibrate drugs (gemfibrozil and fenofibrate), nicotinic acid drugs (acipimox) and the like. However, these drugs acting on a single target point have various unsatisfactory side effects in clinical application, such as severe myopathy and rhabdomyolysis, and hepatotoxicity in the current first ten drugs of the world sold atorvastatin (also known as lipitor) as an HMG-CoA reductase inhibitor; even the new drug lomitapide, which has just been approved by the FDA to be marketed in 12 months 2012 for the treatment of familial hypercholesterolemia, is indicated to be at risk for gastrointestinal reactions and hepatotoxicity. Therefore, the search for lipid-lowering drugs with significant efficacy, safety and reliability is a subject worthy of long-term research by medical workers.
However, from the actual situation of our country, we completely imitate the western countries to find the lead compound from the artificially synthesized product, and create a new lipid-lowering drug with high efficiency and low toxicity, which is difficult to get a major breakthrough in a short period, but the natural product rich in the traditional clinically effective drug has the specific structural diversity and multi-target action mechanism, and is more and more favored by researchers at home and abroad, such as berberine which is the main lipid-lowering active ingredient in the Chinese medicine coptis root.
The action mechanism of traditional Chinese medicine lipid regulation is complex compared with western medicines, adverse reactions are less, and lipid reduction is achieved mainly by reducing absorption of exogenous lipid in intestinal tracts, inhibiting synthesis of endogenous lipid and regulating lipid metabolism. For example, a single Chinese medicine (kudzu root, ginseng, salvia miltiorrhiza, ginkgo leaf and the like) with the function of regulating blood fat; the lipid-lowering natural product can be polysaccharides (fructus Lycii polysaccharide, fructus Cucurbitae Moschatae polysaccharide), flavonoids (dihydrotanshinone, folium Ginkgo flavone) and polyphenols (catechin). In recent years, many folk traditional medicines are found to have good lipid regulating effect and are gradually developed into medicines, for example, a Xuezhikang capsule (main component red yeast) developed by limited northern Weixin biotechnology has completed phase II clinical research in the United states at present, and Jianjiandong subject group of institute of biotechnology of Chinese academy of medicine sciences finds that berberine also has good lipid lowering activity, is completely different from the action mechanism of statin lipid lowering medicines, and theoretically provides a new molecular target for searching for novel lipid lowering medicines. Different from the single-target western medicines which are clinically and frequently adopted at the present stage and easily cause adverse reactions, the multi-target characteristics of the natural medicines are probably the reasons for less toxic and side effects, so the method has epoch significance for the deep exploration and research of the natural medicines.
Disclosure of Invention
In view of the above, the present invention aims to provide a caffeoylquinic acid derivative, and a preparation method and a use thereof, wherein the caffeoylquinic acid derivative has a good lipid-lowering effect.
In view of the above object, the present invention provides a caffeoylquinic acid derivative having a structure represented by general formula (i):
Figure BDA0001941435260000021
in the formula: r6Is an H atom;
R4and R5Is an H atom;
R2and R3Is H atom or propylidene;
R1selected from alkyl amines having 1-18 carbons, aryl amines having 6-10 carbons or alkyl amines having 3-7 carbonsSaturated or unsaturated cyclic amines of carbon atoms.
In some embodiments of the invention, R1Selected from alkylamines containing 3-8 carbons, arylamines containing 7-8 carbons or saturated cyclic amines containing 5-6 carbons.
In some embodiments of the invention, R1Selected from n-butylamino, isobutylamino, n-octylamino, propargylamino, benzylamino, piperidinyl or cyclohexylamino.
The invention also provides a preparation method of the caffeoylquinic acid derivative, which comprises the following steps:
(1) reacting 3-O-caffeoylquinic acid with 2, 2-dimethoxypropane to generate an intermediate;
(2) and carrying out condensation reaction on the intermediate and amine to generate a target compound caffeoylquinic acid derivative.
In some embodiments of the present invention, after step (2), further comprising:
(3): carrying out deprotection reaction on the target compound caffeoylquinic acid derivative.
In some embodiments of the present invention, the method for preparing caffeoylquinic acid derivatives comprises the following steps:
(1) reacting 3-O-caffeoylquinic acid and 2, 2-dimethoxypropane in anhydrous acetone by taking p-toluenesulfonic acid as a catalyst to generate an intermediate shown in a formula (II);
Figure BDA0001941435260000031
(2) the intermediate shown in the formula (II) is subjected to condensation reaction with amine in a mixed solvent of anhydrous acetonitrile and tetrahydrofuran under the condensation condition of BOP and DIEA to generate the target compound caffeoylquinic acid derivative.
In some embodiments of the present invention, after step (2), further comprising:
(3): removing acetonylidene protection from a target compound caffeoylquinic acid derivative in a mixed solution of trifluoroacetic acid, dichloromethane and water.
The invention also provides a pharmaceutical composition, which comprises the caffeoylquinic acid derivative and a medicinal carrier.
The invention also provides application of the caffeoylquinic acid derivatives in preparing a medicament for preventing and/or treating hyperlipidemia.
The invention also provides application of the caffeoylquinic acid derivatives in preparing medicaments for preventing and/or treating atherosclerosis.
From the above, the invention can be seen in that 3-O-caffeoylquinic acid is used as a raw material, the structural skeleton of the 3-O-caffeoylquinic acid is kept, different amino substituent groups are introduced to the carboxyl group at the 1 position, and the hydroxyl groups at the 4 and 5 positions are substituted or exposed by ketal, so that the novel caffeoylquinic acid derivative with lipid-lowering activity is synthesized, the synthesis method is simple and convenient, and the product purity is high. Compared with 3-O-caffeoylquinic acid, the caffeoylquinic acid derivative provided by the invention has better lipid-lowering activity. The invention fully utilizes medicinal plant resources found from natural products, deeply researches and develops to find compounds with unique chemical structures, and finds the lipid-lowering medicament for clinical application.
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FIG. 1 is a graph of the modulating effect of chlorogenic acid and its derivatives on oleic acid-induced lipid accumulation in HepG2 hepatocytes; wherein, A picture shows the regulation effect of caffeoylquinic acid derivatives 3a, 3b, 3c, 3d, 3e and 3f on lipid accumulation caused by oleic acid in HepG2 liver cells; the B picture shows that the caffeoylquinic acid derivatives 4a, 4B, 4c, 4d, 4e and 4f have the regulating effect on lipid accumulation initiated by oleic acid in HepG2 liver cells, CA is chlorogenic acid, S is simvastatin, M is oleic acid, K is a control, and # p <0.001 is very obvious compared with the cells (K) treated by the control group; p <0.05 was significantly different relative to cells treated with oleic acid (M); p <0.01 was significant relative to oleic acid (M) -treated cells; the cells differed significantly with p <0.001 versus oleic acid (M) treated cells.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments below.
The invention provides a caffeoylquinic acid derivative, which has a structure shown in a general formula (I):
Figure BDA0001941435260000041
in the formula: r6Is an H atom;
R4and R5Is an H atom;
R2and R3Is H atom or propylidene;
R1selected from alkylamines containing 1-18 carbons, arylamines containing 6-10 carbons or saturated or unsaturated cyclic amines containing 3-7 carbons.
As an embodiment of the present invention, R1Selected from alkylamines containing 3-8 carbons, arylamines containing 7-8 carbons or saturated cyclic amines containing 5-6 carbons.
As an embodiment of the present invention, R1Selected from n-butylamino, isobutylamino, n-octylamino, propargylamino, benzylamino, piperidinyl or cyclohexylamino.
As an embodiment of the present invention, when R6Is an H atom; r4And R5Is an H atom; r2And R3Is propylidene; the structure shown in the formula (I) is as follows:
Figure BDA0001941435260000051
when R is1Is n-butylamino, and is a tertiary amino,
Figure BDA0001941435260000052
the caffeoylquinic acid derivative is now designated 3 a.
When R is1Is an isobutylamino group, and the like,
Figure BDA0001941435260000053
the caffeoylquinic acid derivative is named 3 b.
When R is1Is a n-octylamino group, and the amino acid is,
Figure BDA0001941435260000054
the caffeoylquinic acid derivative is named 3 c.
When R is1Is a propargylamine group, and is a propargylamine group,
Figure BDA0001941435260000055
the caffeoylquinic acid derivative is named 3 d.
When R is1Is a benzylamino group, and is a benzyl amine group,
Figure BDA0001941435260000056
the caffeoylquinic acid derivative is named 3 e.
When R is1Is a piperidine group, and is a cyclic or cyclic piperidine group,
Figure BDA0001941435260000057
the caffeoylquinic acid derivative is named 3 f.
When R is1Is a cyclohexylamino group, and is a cyclohexylamino group,
Figure BDA0001941435260000058
the caffeoylquinic acid derivative was named 3g at this time.
As an embodiment of the present invention, when R6Is an H atom; r4And R5Is an H atom; r2And R3Is an H atom; the structure shown in the formula (I) is as follows:
Figure BDA0001941435260000061
when R is1Is n-butylamino, and is a tertiary amino,
Figure BDA0001941435260000062
the caffeoylquinic acid derivative is now designated 4 a.
When R is1Is an isobutylamino group, and the like,
Figure BDA0001941435260000063
the caffeoylquinic acid derivative is named 4 b.
When R is1Is a n-octylamino group, and the amino acid is,
Figure BDA0001941435260000064
the caffeoylquinic acid derivative is named 4 c.
When R is1Is a propargylamine group, and is a propargylamine group,
Figure BDA0001941435260000065
the caffeoylquinic acid derivative is named 4 d.
When R is1Is a benzylamino group, and is a benzyl amine group,
Figure BDA0001941435260000066
the caffeoylquinic acid derivative is named 4 e.
When R is1Is a piperidine group, and is a cyclic or cyclic piperidine group,
Figure BDA0001941435260000067
the caffeoylquinic acid derivative is named 4 f.
When R is1Is a cyclohexylamino group, and is a cyclohexylamino group,
Figure BDA0001941435260000068
the caffeoylquinic acid derivative was named 4g at this time.
The invention also provides a preparation method of the caffeoylquinic acid derivative, which comprises the following steps:
(1) reacting 3-O-caffeoylquinic acid with 2, 2-dimethoxypropane to generate an intermediate;
(2) and carrying out condensation reaction on the intermediate and amine to generate a target compound caffeoylquinic acid derivative.
Specifically, the synthetic route of the caffeoylquinic acid derivative is as follows:
(1) synthesis reaction of intermediate 2
Figure BDA0001941435260000071
Taking a compound 1 (3-O-caffeoylquinic acid) as an initial raw material, and reacting 4, 5-hydroxy of the 3-O-caffeoylquinic acid with 2, 2-Dimethyloxypropane (DMP) in anhydrous acetone under the catalysis of p-toluenesulfonic acid (TsOH) to obtain an intermediate 2;
wherein, the structural formula of the 2, 2-dimethoxypropane is as follows:
Figure BDA0001941435260000072
(2) synthesis reaction of target Compound
Figure BDA0001941435260000073
Intermediate 2 was condensed with BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) and DIEA (N, N-diisopropylethylamine) in anhydrous acetonitrile (CH)3CN) and Tetrahydrofuran (THF) to generate a target compound caffeoylquinic acid derivative through a condensation reaction with amine, wherein the target compound caffeoylquinic acid derivative comprises 3a, 3b, 3c, 3d, 3e, 3f and 3 g.
In one embodiment of the present invention, the target compound caffeoylquinic acid derivative of step (2) is subjected to deprotection reaction to obtain the target compounds caffeoylquinic acid derivatives 4a, 4b, 4c, 4d, 4e, 4f and 4 g.
Specifically, the synthetic route is as follows:
Figure BDA0001941435260000081
the caffeoylquinic acid derivatives of the target compounds comprise 3a, 3b, 3c, 3d, 3e, 3f and 3g, and the acetonylidene protection is removed from a mixed solution of trifluoroacetic acid (TFA), Dichloromethane (DCM) and water, so that caffeoylquinic acid derivatives of the target compounds, 4a, 4b, 4c, 4d, 4e, 4f and 4g, are respectively obtained.
The general synthetic route of the target compound caffeoylquinic acid derivative is as follows:
Figure BDA0001941435260000082
wherein, (A) DMP, TsOH, acetone; (B) BOP, DIEA, amines; (C) TFA, DCM, H2O(9:1:1).
Therefore, according to the structural characteristics of the 3-O-caffeoylquinic acid, the hydroxyl at the 4, 5-position of the 3-O-caffeoylquinic acid is reacted with 2, 2-Dimethoxypropane (DMP), so that the hydroxyl at the 4, 5-position of the 3-O-caffeoylquinic acid is substituted by ketal to obtain an intermediate 2; then reacting the intermediate 2 with various amines, and introducing different amino substituent groups on the 1-position carboxyl group to obtain the caffeoylquinic acid derivatives; or the acetonylidene protection is further removed from the obtained caffeoylquinic acid derivative, so that the hydroxyl groups at the 4 and 5 positions are exposed. The preparation method of the caffeoylquinic acid derivative provided by the invention has the advantages of simple and convenient synthesis method and high product purity.
Example 1 preparation of caffeoylquinic acid derivative 3a
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. Adding a catalytic amount of 50mg TsOH (p-toluenesulfonic acid) into the reaction solution, stirring the reaction solution until the reaction solution is clear, reacting at room temperature, monitoring by TLC (thin layer chromatography), and after the reaction is finished, using anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3a
In a 250mL round bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, in an argon atmosphereUnder the condition of gas protection, 70mL of anhydrous mixed solvent THF/CH is added3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, 3mmol of n-butylamine were added dropwise to the reaction mixture until the end of the reaction as monitored by TLC. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 3a as pale yellow powder with a yield of 81%.
1H-NMR(600MHz,DMSO)δ:9.58(s,1H,Ph-OH),9.14(s,1H,Ph-OH),7.71 (t,J＝6.0Hz,1H,NH),7.48(d,J＝15.8Hz,1H,H-7′),7.05(d,J＝1.7Hz,1H,H- 2′),7.00(dd,J＝8.3Hz,1.7Hz,1H,H-6’),6.77(d,J＝8.2Hz,1H,H-5’),6.24(d, J＝15.9Hz,1H,H-8′),5.41(s,1H,H-1),5.37-5.32(m,1H,H-3),4.43-4.41(m, 1H,H-4),4.13-4.11(m,1H,H-5),3.11-3.01(m,2H,NH-CH2),2.26-2.22(m,1H, H-2),1.99-1.94(m,1H,H-2),1.80-1.73(m,2H,H-6),1.42(s,3H,CH3-C-O), 1.39-1.36(m,2H,NH-CH2-CH2),1.26-1.22(m,5H,CH3-C-O,CH2-CH3),0.84(t, J＝7.3Hz,3H,CH2-CH3)；13C-NMR(150MHz,DMSO)δ:175.0,165.9,148.4, 145.6,145.3,125.6,121.4,115.8,114.9,114.1,108.0,76.9,74.1,73.5,70.9,38.2, 37.0,34.5,31.2,28.0,25.9,19.4,13.7；HRMS(ESI):Calcd for[M+Na]+ C23H31NNaO8:472.1947,found 472.1948。
Example 2 preparation of caffeoylquinic acid derivative 4a
(3) Preparation of caffeoylquinic acid derivative 4a
In a 50mL round-bottom flask, accurately weighing 2mmol caffeoylquinic acid derivative 3a, respectively, and adding TFA/DCM/H220mL of a mixed solution of O (v/v ═ 9:1:1) was stirred at room temperature for 0.5 h until the reaction was completed as monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 4a as pale yellow powder in 78% yield.
1H-NMR(600MHz,MeOD)δ:7.58(d,J＝15.9Hz,1H,H-7′),7.05(d,J＝1.9 Hz,1H,H-2′),6.95(dd,J＝8.2Hz,1.9Hz,1H,H-6’),6.78(d,J＝8.1Hz,1H,H- 5’),6.29(d,J＝15.9Hz,1H,H-8′),5.42-5.38(m,1H,H-3),4.24-4.23(m,1H,H- 4),3.72-3.70(m,1H,H-5),3.21-3.19(m,2H,NH-CH2),2.12-2.07(m,2H,H-2), 2.02-2.00(m,1H,H-6),1.95-1.91(m,1H,H-6),1.52-1.47(m,2H,NH-CH2-CH2), 1.36-1.32(m,2H,CH2-CH3),0.93(t,J＝7.4Hz,3H,CH2-CH3)；13C-NMR(150 MHz,MeOD)δ:176.6,169.0,149.6,147.0,146.8,127.8,122.9,116.5,115.4, 115.2,77.8,74.4,72.7,71.9,40.0,39.9,38.7,32.6,21.0,14.1；HRMS(ESI):Calcd for[M+Na]+C20H27NNaO8:432.1634,found 432.1636。
Example 3 preparation of caffeoylquinic acid derivative 3b
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. Adding a catalytic amount of 50mg TsOH (p-toluenesulfonic acid) into the reaction solution, stirring the reaction solution until the reaction solution is clear, reacting at room temperature, monitoring by TLC (thin layer chromatography), and after the reaction is finished, using anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3b
In a 250mL round-bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, and 70mL of anhydrous mixed solvent THF/CH is added under the protection of argon3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, 3mmol of isobutylamine was added dropwise to the reaction until the end of the reaction monitored by TLC. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 3b as a pale yellow powder in 77% yield.
1H-NMR(600MHz,DMSO)δ:7.70(t,J＝6.1Hz,1H,NH),7.47(d,J＝15.8 Hz,1H,H-7′),7.04(d,J＝2.0Hz,1H,H-2′),7.00(dd,J＝8.2Hz,2.0Hz,1H,H- 6’),6.76(d,J＝8.2Hz,1H,H-5’),6.24(d,J＝15.9Hz,1H,H-8′),5.47(br,1H,H- 1),5.37-5.33(m,1H,H-3),4.43-4.41(m,1H,H-4),4.14-4.11(m,1H,H-5), 2.94-2.86(m,2H,NH-CH2),2.26-2.22(m,1H,H-2),1.99-1.96(m,1H,H-2), 1.80-1.75(m,2H,H-6),1.74-1.69(m,1H,NH-CH2-CH),1.42(s,3H,CH3-C-O), 1.26(s,3H,CH3-C-O),0.82-0.80(m,6H,2×CH3)；13C-NMR(150MHz,DMSO) δ:175.1,165.9,148.5,145.6,145.4,125.6,121.4,115.8,114.9,114.1,108.0,76.9, 74.2,73.6,70.9,45.9,37.1,34.4,28.1,26.0,20.0；HRMS(ESI):Calcd for[M+ Na]+C23H31NNaO8:472.1947,found 472.1946。
Example 4 preparation of caffeoylquinic acid derivative 4b
(3) Preparation of caffeoylquinic acid derivative 4b
In a 50mL round-bottom flask, accurately weighing 2mmol caffeoylquinic acid derivative 3b, respectively, and adding TFA/DCM/H220mL of a mixed solution of O (v/v ═ 9:1:1) was stirred at room temperature for 0.5 h until the reaction was completed as monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 4b as pale yellow powder with a yield of 85%.
1H-NMR(600MHz,MeOD)δ:7.57(d,J＝15.7Hz,1H,H-7′),7.05(s,1H,H- 2′),6.99-6.89(m,1H,H-6’),6.78(d,J＝7.7Hz,1H,H-5’),6.29(d,J＝15.7Hz, 1H,H-8′),5.46-5.37(m,1H,H-3),4.30-4.18(m,1H,H-4),3.78-3.66(m,1H,H- 5),3.09-2.95(m,2H,NH-CH2),2.11-1.94(m,1H,H-2,6),1.85-1.73(m,1H, NH-CH2-CH),0.94-0.84(m,6H,2×CH3)；13C-NMR(150MHz,MeOD)δ:176.7, 169.0,149.5,147.0,146.7,127.7,122.9,116.5,115.3,115.2,77.8,74.3,72.6,71.9, 47.6,40.0,38.7,29.6,20.3；HRMS(ESI):Calcd for[M+Na]+C20H27NNaO8: 432.1634,found 432.1638.
Example 5 preparation of caffeoylquinic acid derivative 3c
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. To the reaction solution was added a catalytic amount of 50mg of TsOH (p-toluenesulfonic acid)) Stirring the mixture to react until the reaction solution is clear, reacting at room temperature, monitoring by TLC, and reacting with anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3c
In a 250mL round-bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, and 70mL of anhydrous mixed solvent THF/CH is added under the protection of argon3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, 3mmol of n-octylamine were added dropwise to the reaction solution until the end of the reaction as monitored by TLC. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 3c as pale yellow powder in 82% yield.
1H-NMR(600MHz,DMSO)δ:7.74(t,J＝5.9Hz,1H,NH),7.47(d,J＝15.8 Hz,1H,H-7′),7.04(d,J＝2.0Hz,1H,H-2′),7.00(dd,J＝8.2Hz,2.0Hz,1H, H-6’),6.76(d,J＝8.2Hz,1H,H-5’),6.24(d,J＝15.9Hz,1H,H-8′),5.44(br,1H, H-1),5.36-5.31(m,1H,H-3),4.43-4.40(m,1H,H-4),4.13-4.11(m,1H,H-5), 3.10-2.98(m,2H,NH-CH2),2.25-2.22(m,1H,H-2),1.97-1.94(m,1H,H-2), 1.75-1.74(m,2H,H-6),1.41(s,3H,CH3-C-O),1.40-1.37(m,2H,NH-CH2-CH2), 1.25(s,3H,CH3-C-O),1.25-1.19(m,10H,(CH2)5-CH3),0.83(t,J＝7.1Hz,3H, (CH2)5-CH3)；13C-NMR(150MHz,DMSO)δ:174.9,165.8,148.4,145.5,145.2, 125.5,121.3,115.7,114.8,114.0,107.9,76.8,73.9,73.4,70.8,38.4,37.0,34.5, 31.1,28.9,28.6,28.5,27.9,26.1,25.8,22.0,13.8；HRMS(ESI):Calcd for[M+ Na]+C27H39NNaO8:528.2573,found 528.2578。
EXAMPLE 6 preparation of caffeoylquinic acid derivative 4c
(3) Preparation of caffeoylquinic acid derivative 4c
In a 50mL round-bottom flask, accurately weighing 2mmol caffeoylquinic acid derivative 3c, and adding TFA/DCM/H2Mixed solution of O (v/v ═ 9:1:1)20mL, stir the reaction at room temperature for 0.5 h until TLC monitors the end of the reaction. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 4c as pale yellow powder with a yield of 76%.
1H-NMR(400MHz,MeOD)δ:7.58(d,J＝15.9Hz,1H,H-7′),7.05(d,J＝1.9 Hz,1H,H-2′),6.95(dd,J＝8.2Hz,1.9Hz,1H,H-6’),6.78(d,J＝8.2Hz,1H,H- 5’),6.29(d,J＝15.9Hz,1H,H-8′),5.43-5.37(m,1H,H-3),4.24-4.23(m,1H,H- 4),3.72-3.69(m,1H,H-5),3.20-3.17(m,2H,NH-CH2),2.13-1.90(m,1H,H-2, 6),1.52-1.49(m,2H,NH-CH2-CH2),1.34-1.26(m,10H,(CH2)5-CH3),0.87(t,J ＝7.1Hz,3H,-CH3)；13C-NMR(100MHz,MeOD)δ:176.6,169.0,149.6,147.0, 146.8,127.8,123.0,116.5,115.3,115.1,77.7,74.4,72.7,72.0,40.2,40.0,38.7, 33.0,30.5,30.4,27.9,23.7,14.4；HRMS(ESI):Calcd for[M+Na]+C24H35NNaO8:488.2260,found 488.2252。
Example 7 preparation of caffeoylquinic acid derivative 3d
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. Adding a catalytic amount of 50mg TsOH (p-toluenesulfonic acid) into the reaction solution, stirring the reaction solution until the reaction solution is clear, reacting at room temperature, monitoring by TLC (thin layer chromatography), and after the reaction is finished, using anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3d
In a 250mL round-bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, and 70mL of anhydrous mixed solvent THF/CH is added under the protection of argon3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, 3mmol propargylamine was added dropwise to the reaction until TLC monitoring of the reaction was complete. Removing solvent and residue by evaporation under reduced pressureThe residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 3d as a pale yellow powder in 75% yield.
1H-NMR(600MHz,DMSO)δ:8.16(t,J＝5.8Hz,1H,NH),7.47(d,J＝15.8 Hz,1H,H-7′),7.04(d,J＝2.0Hz,1H,H-2′),7.00(dd,J＝8.2Hz,2.0Hz,1H,H- 6’),6.76(d,J＝8.2Hz,1H,H-5’),6.24(d,J＝15.8Hz,1H,H-8′),5.50(s,1H,H-1), 5.35-5.31(m,1H,H-3),4.43-4.41(m,1H,H-4),4.14-4.12(m,1H,H-5),3.84(dd, J＝5.8Hz,2.5Hz,2H,NH-CH2),3.03(t,J＝2.5Hz,1H,CCH),2.25-2.22(m,1H, H-2),2.00-1.95(m,1H,H-2),1.79-1.70(m,2H,H-6),1.42(s,3H,CH3-C-O), 1.26(s,3H,CH3-C-O)；13C-NMR(150MHz,DMSO)δ:175.3,166.0,148.5,145.7, 145.5,125.7,121.5,115.9,114.9,114.2,108.2,81.2,76.9,74.2,73.6,72.6,70.9, 37.0,34.3,28.4,28.1,26.0；HRMS(ESI):Calcd for[M+Na]+C22H25NNaO8: 454.1478,found 454.1480。
EXAMPLE 8 preparation of caffeoylquinic acid derivative 4d
(3) Preparation of caffeoylquinic acid derivative 4d
In a 50mL round-bottom flask, accurately weighing 2mmol caffeoylquinic acid derivative 3d, respectively, and adding TFA/DCM/H220mL of a mixed solution of O (v/v ═ 9:1:1) was stirred at room temperature for 0.5 h until the reaction was completed as monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 4d as pale yellow powder with a yield of 69%.
1H-NMR(400MHz,MeOD)δ:7.57(d,J＝15.9Hz,1H,H-7′),7.11-7.00(m, 1H,H-2′),6.99-6.89(m,1H,H-6’),6.78(d,J＝8.0Hz,1H,H-5’),6.29(d,J＝15.9 Hz,1H,H-8′),5.43-5.37(m,1H,H-3),4.29-4.19(m,1H,H-4),4.03-4.92(m,2H, NH-CH2),3.74-3.71(m,1H,H-5),2.61-2.49(m,1H,CCH),2.15-1.95(m,4H,H- 2,6)；13C-NMR(100MHz,MeOD)δ:176.5,169.0,149.5,147.0,146.7,127.7, 123.0,116.5,115.3,115.1,80.5,77.8,74.3,72.5,72.1,71.8,39.8,38.5,29.4； HRMS(ESI):Calcd for[M+Na]+C19H21NNaO8:414.1165,found 414.1667。
EXAMPLE 9 preparation of caffeoylquinic acid derivative 3e
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. Adding a catalytic amount of 50mg TsOH (p-toluenesulfonic acid) into the reaction solution, stirring the reaction solution until the reaction solution is clear, reacting at room temperature, monitoring by TLC (thin layer chromatography), and after the reaction is finished, using anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3e
In a 250mL round-bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, and 70mL of anhydrous mixed solvent THF/CH is added under the protection of argon3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, 3mmol of benzylamine were added dropwise to the reaction solution until TLC monitoring of the reaction was complete. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 3e as pale yellow powder in 79% yield.
1H-NMR(600MHz,DMSO)δ:8.32(t,J＝6.2Hz,1H,NH),7.48(d,J＝15.8 Hz,1H,H-7′),7.31-7.28(m,2H,Ph-H),7.24-7.20(m,3H,Ph-H),7.05(d,J＝2.0 Hz,1H,H-2′),7.01(dd,J＝8.2Hz,2.0Hz,1H,H-6’),6.77(d,J＝8.2Hz,1H,H- 5’),6.25(d,J＝15.9Hz,1H,H-8′),5.55(br,1H,H-1),5.39-5.35(m,1H,H-3), 4.45-4.42(m,1H,H-4),4.32-4.25(m,2H,NH-CH2),4.15-4.13(m,1H,H-5), 2.29-2.25(m,1H,H-2),2.04-2.01(m,1H,H-2),1.84-1.76(m,2H,H-6),1.43(s, 3H,CH3-C-O),1.26(s,3H,CH3-C-O)；13C-NMR(150MHz,DMSO)δ:175.2, 165.8,148.4,145.5,145.3,139.5,128.1,126.9,126.7,125.5,121.3,115.7,114.8, 114.0,108.0,76.8,74.1,73.4,70.8,42.0,37.0,34.5,27.9,25.8；HRMS(ESI): Calcd for[M+Na]+C26H29NNaO8:506.1791,found 506.1790。
EXAMPLE 10 preparation of caffeoylquinic acid derivative 4e
(3) Preparation of caffeoylquinic acid derivative 4e
In a 50mL round-bottom flask, accurately weighing 2mmol caffeoylquinic acid derivative 3e, respectively, and adding TFA/DCM/H220mL of a mixed solution of O (v/v ═ 9:1:1) was stirred at room temperature for 0.5 h until the reaction was completed as monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 4e as pale yellow powder in 73% yield.
1H-NMR(600MHz,MeOD)δ:7.58(d,J＝15.9Hz,1H,H-7′),7.32-7.22(m, 5H,Ph-H),7.05(s,1H,H-2′),6.96-6.94(m,1H,H-6’),6.78(d,J＝8.1Hz,1H,H- 5’),6.29(d,J＝15.8Hz,1H,H-8′),5.45-5.39(m,1H,H-3),4.39(m,2H,NH-CH2), 4.26-4.25(m,1H,H-4),3.73-3.69(m,1H,H-5),2.17-1.97(m,4H,H-2,6)；13C- NMR(150MHz,MeOD)δ:176.8,169.0,149.5,147.0,146.8,139.9,129.5,128.2, 128.2,128.0,122.9,116.5,115.4,115.2,77.9,74.4,72.7,71.9,43.8,40.0,38.8； HRMS(ESI):Calcd for[M+Na]+C23H25NNaO8:466.1448,found 466.1484。
EXAMPLE 11 preparation of caffeoylquinic acid derivative 3f
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. Adding a catalytic amount of 50mg TsOH (p-toluenesulfonic acid) into the reaction solution, stirring the reaction solution until the reaction solution is clear, reacting at room temperature, monitoring by TLC (thin layer chromatography), and after the reaction is finished, using anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3f
In a 250mL round-bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, and 70mL of anhydrous mixed solvent THF/CH is added under the protection of argon3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, the reaction mixture wasPiperidine 3mmol was added dropwise until the end of the reaction as monitored by TLC. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 3f as pale yellow powder in 64% yield.
1H-NMR(600MHz,DMSO)δ:9.59(s,1H,Ph-OH),9.15(s,1H,Ph-OH),7.48 (d,J＝15.8Hz,1H,H-7′),7.04(d,J＝1.5Hz,1H,H-2′),7.00(dd,J＝8.1Hz,1.5 Hz,1H,H-6’),6.77(d,J＝8.0Hz,1H,H-5’),6.22(d,J＝15.9Hz,1H,H-8′),5.62 (s,1H,H-1),5.32-5.29(m,1H,H-3),4.45-4.42(m,1H,H-4),4.08-4.06(m,1H, H-5),3.97-3.59(m,2H,NH-CH2),3.55-3.43(m,1H,NH-CH),3.35-3.17(m,1H, NH-CH),2.33-2.30(m,1H,H-2),2.01-1.98(m,1H,H-2),1.90-1.86(m,2H,H-6), 1.58-1.50(m,2H,CH2),1.49-1.37(m,2H,CH3-C-O,(CH2)2),1.25(m,3H,CH3- C-O)；13C-NMR(150MHz,DMSO)δ:171.5,165.8,148.5,145.6,145.4,125.5, 121.3,115.8,114.8,114.0,108.0,76.1,74.8,73.2,70.6,37.0,36.8,34.5,29.0,27.9, 25.8,25.5,24.2；HRMS(ESI):Calcd for[M+Na]+C24H31NNaO8:484.1947, found 484.1949。
EXAMPLE 12 preparation of caffeoylquinic acid derivative 4f
(3) Preparation of caffeoylquinic acid derivative 4f
In a 50mL round-bottom flask, accurately weighing 2mmol caffeoylquinic acid derivative 3f, respectively, and adding TFA/DCM/H220mL of a mixed solution of O (v/v ═ 9:1:1) was stirred at room temperature for 0.5 h until the reaction was completed as monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give caffeoylquinic acid derivative 4f as pale yellow powder with a yield of 61%.
1H-NMR(600MHz,MeOD)δ:7.57(d,J＝15.9Hz,1H,H-7′),7.05(d,J＝1.9 Hz,1H,H-2′),6.95(dd,J＝8.2Hz,2.0Hz,1H,H-6’),6.78(d,J＝8.2Hz,1H,H- 5’),6.26(d,J＝15.9Hz,1H,H-8′),5.36-5.33(m,1H,H-3),4.28-4.27(m,1H,H- 4),4.06-3.79(m,2H,NH-CH2),3.73-3.71(m,1H,H-5),3.63-3.38(m,2H,NH- CH2),2.33-2.01(m,4H,H-2,6),1.68-1.61(m,2H,CH2),1.60-1.48(m,4H, (CH2)2),1.90-1.86(m,2H,H-6),1.58-1.50(m,2H,CH2),1.49-1.37(m,2H, CH3-C-O,(CH2)2)；13C-NMR(150MHz,MeOD)δ:173.2,168.8,149.6,147.2, 146.8,127.8,123.0,116.5,115.3,115.2,78.6,73.3,72.4,71.6,40.0,39.2,38.7, 30.7,25.6；HRMS(ESI):Calcd for[M+Na]+C21H27NNaO8:444.1634,found 444.1637。
EXAMPLE 13 preparation of caffeoylquinic acid derivatives 3g
(1) Preparation of intermediate 2
In a 250mL round-bottom flask, 7.0g (19.8mmol) of 3-O-caffeoylquinic acid (Compound 1) was accurately weighed, 60mL of anhydrous acetone and 40mL of DMP (2, 2-dimethoxypropane) were added, and the reaction was stirred to form a suspension. Adding a catalytic amount of 50mg TsOH (p-toluenesulfonic acid) into the reaction solution, stirring the reaction solution until the reaction solution is clear, reacting at room temperature, monitoring by TLC (thin layer chromatography), and after the reaction is finished, using anhydrous Na2CO3And neutralizing until the pH value is 5-6, performing suction filtration, performing reduced pressure evaporation to remove the solvent, and purifying the residue by silica gel column chromatography to obtain an intermediate 2 with the yield of 87%.
(2) Preparation of caffeoylquinic acid derivative 3g
In a 250mL round-bottom flask, exactly 21.2 g (3mmol) of intermediate and 1.5g (3mmol) of BOP are weighed, and 70mL of anhydrous mixed solvent THF/CH is added under the protection of argon3CN (v/v ═ 3:2) was stirred until dissolved. After addition of 0.8g (6mmol) of DIEA, 3mmol of cyclohexylamine were added dropwise to the reaction mixture until the end of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3g of caffeoylquinic acid derivative as a pale yellow powder with a yield of 71%.
1H-NMR(400MHz,DMSO)δ:7.47(d,J＝15.8Hz,1H,H-7′),7.38(d,J＝8.2 Hz,1H,NH),7.04-6.99(m,2H,H-2′,6’),6.76(d,J＝8.1Hz,1H,H-5’),6.24(d,J ＝15.8Hz,1H,H-8′),5.44(br,1H,H-1),5.37-5.30(m,1H,H-3),4.42-4.41(m,1H, H-4),4.14-4.11(m,1H,H-5),3.51-3.49(m,1H,NH-CH),2.25-2.20(m,1H,H-2), 1.97-1.91(m,1H,H-2),1.77-1.75(m,2H,H-6),1.67-1.65(m,4H,CH(CH2)2), 1.41(s,3H,CH3-C-O),1.26-1.10(m,9H,CH3-C-O,(CH2)3)；13C-NMR(100 MHz,DMSO)δ:174.1,165.8,148.4,145.5,145.3,125.5,121.3,115.7,114.8, 114.0,108.0,76.8,74.0,73.5,70.9,47.4,37.0,34.4,32.1,28.0,25.9,25.1,24.4； HRMS(ESI):Calcd for[M+Na]+C25H33NNaO8:498.2104,found 498.2106。
EXAMPLE 14 preparation of caffeoylquinic acid derivative 4g
(3) Preparation of caffeoylquinic acid derivative 4g
In a 50mL round-bottom flask, 3g of 2mmol caffeoylquinic acid derivatives are accurately weighed, respectively, and TFA/DCM/H is added220mL of a mixed solution of O (v/v ═ 9:1:1) was stirred at room temperature for 0.5 h until the reaction was completed as monitored by TLC. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4g of caffeoylquinic acid derivative as pale yellow powder in a yield of 64%.
1H-NMR(600MHz,MeOD)δ:7.57(d,J＝15.9Hz,1H,H-7′),7.05(d,J＝2.0 Hz,1H,H-2′),6.95(dd,J＝8.2Hz,2.0Hz,1H,H-6’),6.78(d,J＝8.2Hz,1H,H- 5’),6.29(d,J＝16.0Hz,1H,H-8′),5.42-5.36(m,1H,H-3),4.24-4.22(m,1H,H- 4),3.72-3.69(m,1H,H-5),3.65-3.58(m,1H,NH-CH),2.12-1.89(m,4H,H-2,6), 1.84-1.82(m,2H,CH2),1.77-1.73(m,2H,CH2),1.65-1.58(m,2H,CH2), 1.40-1.34(m,2H,CH2),1.26-1.23(m,2H,CH2)；13C-NMR(150MHz,MeOD)δ: 175.7,169.0,149.6,147.0,146.8,127.8,122.9,116.5,115.4,115.2,77.6,74.4, 72.7,72.0,49.6,40.0,38.7,33.6,30.7,26.5,26.1；HRMS(ESI):Calcd for[M+ Na]+C22H29NNaO8:458.1791,found 458.1795。
Test example 1 biological Activity test of Caffeoylquinic acid derivatives
1.1 cytology methods
The human liver HepG2 cell line was cultured in DMEM medium containing 10% fetal bovine serum and penicillin/streptomycin (100. mu.g/mL) at 37 ℃ in 5% CO2Cultured in an incubator. Stimulating the cells for 12 hours by using 100 mu mol/L mixed solution of oleic acid (M) and palmitic acid when the cells grow to 70-80% of the culture dish, and preparing a lipid accumulation model; followed by administration of different caffeoylquinic acid derivatives (10 μmol/L) and chlorogenic acid (namely 3-O-Caffeoylquinic Acid) (CA) and simvastatin (S) with the same concentration, and a blank group (K) control is added, and the two are incubated for 24 hours. After the experiment, the caffeoylquinic acid compounds are stained with oil red O, and the absorbance (A) value is measured at 358nm by a spectrophotometer to observe the effective compounds for inhibiting lipid accumulation in the caffeoylquinic acid compounds. Each experiment was repeated 3 times, and the data were expressed as three independent experiments
Figure BDA0001941435260000171
The value is obtained.
1.2 results of lipid-lowering Activity
The lipid-lowering effect of chlorogenic acid and its derivatives on oleic acid-induced lipid accumulation in HepG2 hepatocytes was examined using an oil red O staining assay. Results of oil red O staining indicate that some derivatives have moderate to good regulatory effects on oleic acid-induced lipid accumulation in HepG2 hepatocytes. As shown in FIG. 1, preliminary testing at 10. mu. mol/L showed that caffeoylquinic acid derivatives 3d, 3f, 3g, 4a and 4c better mitigated lipid-lowering effects of HepG2 cells. The caffeoylquinic acid derivatives 3d, 3g, 4a and 4c have better regulation effect on HepG2 liver cells than Chlorogenic Acid (CA). After treatment with 10. mu. mol/L caffeoylquinic acid derivatives 3d, 3f and 3g in FIG. 1A, respectively, the absorbance decreased from 0.261 (treated with oleic acid alone) to 0.249,0.255 and 0.249. In FIG. 1B, the absorbance was reduced from 0.282 (oleic acid alone) to 0.271,0.267,0.270,0.273,0.271 and 0.272 after treatment with 10. mu. mol/L of derivatives 4a, 4c, 4d, 4e, 4f and 4g, respectively. Among them, caffeoylquinic acid derivatives 3d, 3g, 4c and 4d showed stronger modulating effects than other derivatives after 24 hours of treatment, which indicates that 3d, 3g, 4c and 4d are worthy of intensive study as potential lipid-modulating compounds that modulate oleic acid to cause lipid accumulation in HepG2 hepatocytes.
1.3 Structure-activity relationship analysis
Preliminary structure-activity relationship (SARs) analysis showed that amide derivatives of chlorogenic acid with ketal-substituted 4,5 hydroxyl groups were slightly less active than the amide derivatives with naked 4,5 hydroxyl groups compared to simvastatin (S) and Chlorogenic Acid (CA) positive controls. In addition, the 3d, 4d, 3f, 4f, 3g and 4g derivatives containing propargylamine, piperidyl and cyclohexylamine groups can better regulate lipid accumulation after oleic acid treatment, and show that the introduction of propargylamine, piperidyl and cyclohexylamine groups can improve lipid accumulation. Among them, derivatives 3d and 4d showed stronger lipid-lowering effect compared to other compounds, which means that propargylamine group is a favorable substituent for regulating lipid accumulation in HepG2 hepatocytes. However, the derivatives 3b and 4b (including the isobutylamino group) were less active, indicating that the introduction of the isobutylamino group was not favorable for the derivatives to exert lipid-lowering activity. In addition, the above derivatives show lipid-lowering effect in fig. 1, which shows that the 1-position carboxyl group and the 4, 5-position hydroxyl groups of chlorogenic acid are not essential groups for regulating lipid effect, and the influence of different amino substituents on the 1-position carboxyl group on lipid-lowering activity is more obvious.
Those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the inventive idea, also technical features in the above embodiments or in different embodiments may be combined and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity. Therefore, any omissions, modifications, substitutions, improvements and the like that may be made without departing from the spirit and principles of the invention are intended to be included within the scope of the invention.

Claims (8)

1. A caffeoylquinic acid derivative, which is characterized by having a structure shown in a general formula (I):
Figure FDA0002958432880000011
in the formula: r6Is an H atom;
R4and R5Is an H atom;
R2and R3Is propylidene, R1 is selected from propargylamine or cyclohexylamine;
R2and R3Is H atom, R1 is selected from propargylamine group.
2. A process for the preparation of caffeoylquinic acid derivatives, as claimed in claim 1, comprising the steps of:
(1) reacting 3-O-caffeoylquinic acid with 2, 2-dimethoxypropane to generate an intermediate;
(2) and carrying out condensation reaction on the intermediate and amine to generate a target compound caffeoylquinic acid derivative.
3. The process for producing a caffeoylquinic acid derivative according to claim 2, further comprising, after the step (2):
(3): carrying out deprotection reaction on the target compound caffeoylquinic acid derivative.
4. The process for producing a caffeoylquinic acid derivative according to claim 2, which comprises the steps of:
(1) reacting 3-O-caffeoylquinic acid and 2, 2-dimethoxypropane in anhydrous acetone by taking p-toluenesulfonic acid as a catalyst to generate an intermediate shown in a formula (II);
Figure FDA0002958432880000012
Figure FDA0002958432880000021
(2) the intermediate shown in the formula (II) is subjected to condensation reaction with amine in a mixed solvent of anhydrous acetonitrile and tetrahydrofuran under the condensation condition of BOP and DIEA to generate the target compound caffeoylquinic acid derivative.
5. The process for producing a caffeoylquinic acid derivative according to claim 4, which further comprises, after the step (2):
(3): removing acetonylidene protection from a target compound caffeoylquinic acid derivative in a mixed solution of trifluoroacetic acid, dichloromethane and water.
6. A pharmaceutical composition comprising the caffeoylquinic acid derivative according to claim 1 and a pharmaceutically acceptable carrier.
7. Use of the caffeoylquinic acid derivatives of claim 1 in the preparation of medicaments for preventing and/or treating hyperlipidemia.
8. Use of the caffeoylquinic acid derivatives of claim 1 in the preparation of a medicament for the prevention and/or treatment of atherosclerosis.
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