CN107163096B - Troxerutin amide derivative and synthesis method and application thereof - Google Patents

Abstract

The invention discloses a troxerutin amide derivative and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry.A troxerutin vinyl ester is taken as a raw material, and the troxerutin vinyl ester reacts with 1,2,3, 4-tetrahydroisoquinoline compounds or phenethylamine, 4-fluoro-phenethylamine and benzylamine compounds respectively in ionic liquid at the reaction temperature of 40 ℃ of ~ 70 ℃ to obtain the troxerutin amide derivative.

Description

Troxerutin amide derivative and synthesis method and application thereof

Technical Field

The invention relates to a flavonoid compound, in particular to a troxerutin amide compound and a preparation method and application thereof, belonging to the field of pharmaceutical chemistry.

Background

The flavone is a polyphenol compound and widely exists in roots, stems, leaves, flowers and fruits of higher plants, the compound not only has good inhibitory action and analgesic action on cardiovascular and cerebrovascular diseases and abnormal digestive system, but also has the functions of scavenging free radicals, resisting tumors, viruses, oxidation, mutation, bacteria and regulating immunity (Harborne, JB; Williams, CA. Advances in flavanoid research site 1992J. Phytochemistry,2000,55, 481-504; Liuxing rain, Sun Zi, peripheral allergy, pharmacological activity of natural flavonoid compounds and separation and extraction [ J ] Chinese medicines and clinics, 2014,14(5), 621-624). However, due to the rigid planar structure and the tight arrangement among molecules, most flavonoid natural products have low water solubility or lipid solubility, which results in low utilization rate of physiological activity and limits the development and application of flavonoid natural products (Yanxi, Liu Hui Qing, Zhongqing, etc.. flavonoid compound physiological activity and synthesis research progress [ J ] organic chemistry, 2008,28(9), 1534-. The modification method mainly comprises substitution reaction, Mannich reaction, esterification reaction, hydroxylation reaction, glycosylation reaction and the like. For example, dibromo-alkanes with different carbon chain lengths are used to perform electrophilic substitution reaction with chrysin at the 7-OH position, active groups are introduced, and then the substituted dibromo-alkanes and chrysin are subjected to ammonolysis reaction with morpholine, N-methylpiperazine, piperazine and N, N-dimethylamine to synthesize novel nitrogen-containing derivatives of chrysin (Suresh Babu K, Hari Babu T, Srinivas PV, et al.Synthesis and biological evaluation of novel C (7) modified chrysin and antibody agents [ J ]. bioorg.Med.chem.Lett.,2006,16, 221-224). Zeng and the like have used electrophilic substitution reaction to synthesize flavonoid derivatives with piperazine substituent, and have shown in vivo and in vitro antitumor property (Zeng S, Liu W, Nie FF, ethyl. LYG-202, a new flavone with a piperazine mutation, show in vivo and in vitro properties [ J ]. biochem. Bioph. Res. Co.,2009,385, 551) 556); babu et al synthesized a series of 8-aminomethyl derivatives from formaldehyde and primary and secondary amines and oroxylin by Mannich reaction (Babu TH, Rama Subba Rao V, Ashok K, et al. Synthesis and biological evaluation of novel 8-aminomethylated oxolin A analogues as a-glucopyranosase inhibitors [ J ]. bioorg.Med.chem.Let,2008,18, 1659-1662); bhullar et al catalyze the esterification of isoquercitrin with fatty acid in acetone and tert-amyl alcohol by Novozym 435 to selectively synthesize isoquercitrin-6' -O-ester group derivatives. The esterified product has greatly improved lipid solubility, oxidation resistance and antiproliferative activity (Ziaullah; Bhullar, Khushwant S.; Warnakularsuriya, Sumudu N.et. Bhullar K S, Warnakularsuriya S N, Rupasinghe H V. biocatalytic synthesis, structural emulsification, antioxidant and cationic inhibition activity of fatty acid acyl derivatives of phthalic and isoquercitin [ J ]. bioorg. Med. chem. Let,2013,21(3): 684-. Korean is better to take 6 flavones (chrysin, apigenin, daidzein and the like) as raw materials, the flavones and phosphoramidate are subjected to esterification reaction at flavone C-7 hydroxyl, and the synthesized flavone phosphoramidate derivatives are evaluated by HIV activity and possibly have antitumor activity (outstanding Korean, design and synthesis of six flavone 7-amino phosphoric acid vinegar derivatives [ D ]. Dalian, university of continental project, 2012); modolo et al catalyze glycosylation reactions of flavones and isoflavones by glycosyltransferase. (Modolo L V, LiL, Pan H, et al. Crystal structures of glycosylation transfer UGT78G1 recent the molecular basis for glycosylation and glycosylation of (iso) textures [ J ] J.mol.biology,2009,392(5):1292 and 1302).

Ionic liquids, as a green solvent, are widely used in organic synthesis due to their good properties such as low vapor pressure, wide liquid range, high ionic conductivity, high thermal stability, and solubility of most compounds. Recently, ionic liquids have been reported as solvents for the modification of natural products, and Katsoura et al have studied enzymes in ionic liquids [ BMIM ]][BF₄]When the rutin and the naringin are catalyzed to perform acylation reaction when being used as a solvent, the use of the ionic liquid greatly improves the reaction conversion rate and the regioselectivity of the enzyme (Katsoura M H, Polydera A C, Tsonins L, et al. use of ionic liquids as a medium for the biochemical preparation of flavonoid derivative antioxidant potential [ J]J.Biotechnol.,2006,123(4): 491-503). Wang reports that ionic liquid and buffer solvent are used as co-solvents, which is beneficial to enzyme to selectively hydrolyze rutin and convert to obtain isoquercitrin (Wang, J, Sun, GX, Yu, L et al. enhancement of the selective enzymatic biological transformation of a pigment to an isoquercitrin using an ionic liquid a-solvent [ J, Sun, GX, Yu, L et al]Biores.Technol.2012,128: 156-. The catalytic synthesis of troxerutin amide derivatives by using ionic liquid is not reported. Compared with the chemical catalysis and enzyme catalysis modified flavonoid compounds reported in the literature, the ionic liquid is used as a solvent and a reaction system of the catalyst, so that the dosage of the catalyst can be greatly saved, and due to the characteristics of simple preparation, low price, easy recovery and the like of the ionic liquid, the synthesis cost can be reduced, and the post-treatment operation can be simplified. The reaction system using the cheap ionic liquid as the catalyst also provides a new way for the structural modification of the flavonoid compound.

Disclosure of Invention

The invention aims to provide series of troxerutin amide derivatives; the other purpose is to provide a preparation method of the troxerutin amide derivative, which uses the ionic liquid as a catalyst and a solvent, has mild reaction conditions, is simple and feasible, and has few byproducts.

The troxerutin amide derivative has the following structure:

n- (4-fluoro) phenethyl/benzyl troxerutin amide derivatives (I)

Tetrahydroisoquinoline-containing troxerutin amide derivatives (II)

In the general formula I, II, n represents the number of methylene groups and is respectively 2,3,4,5,6,7,8,10 and 11. In the general formula I, R' is phenethyl, 4-fluorophenethyl and benzyl respectively; r₁And R₂Are respectively-H, -OCH₃The same or different.

Preferred compounds of formula I are the following:

(1)

n is 3,4,5, 7.

(2)

n is 3,4, 5.

(3)

n is 3,4, 5.

Preferred compounds in formula II are the following:

(1)R₁＝H，R₂n is a number of atoms of 3, 5, 10,

(2)R₁＝OCH₃，R₂＝OCH₃n is a number of 4, 8,

(3)R₁＝H，R₂＝OCH₃n is a number of 3, 5,7。

the synthetic route of the compound is as follows:

the synthesis method of the N- (4-fluoro) phenethyl/benzyl troxerutin amide derivative (I) is realized by the following steps:

troxerutin and fatty acid divinyl ester react at 40-60 ℃ in the presence of subtilisin catalysis and pyridine as a reaction medium, and after the reaction is finished, troxerutin vinyl ester is obtained by column separation.

Troxerutin vinyl esters with different chain lengths react with phenethylamine, 4-fluoro-phenethylamine or benzylamine compounds at 40-70 ℃ respectively in the presence of ionic liquid. After the reaction is finished, extracting by using an organic solvent, concentrating the extract under reduced pressure, and separating by using column chromatography to obtain the N-phenethyl/benzyl troxerutin amide derivative (I).

The molar ratio of the troxerutin vinyl ester to the amine compound is 1: 2-10.

The synthesis method of the tetrahydroisoquinoline-containing troxerutin amide derivative (II) is realized by the following mode:

the ionic liquid is used as a reaction medium, and troxerutin vinyl ester and 1,2,3, 4-tetrahydroisoquinoline compounds are used as reaction substrates and react at the temperature of 40-70 ℃. After the reaction is finished, extracting the product by using an organic solvent, concentrating, and separating by using column chromatography to obtain the tetrahydroisoquinoline troxerutin amide derivative (II).

The molar ratio of the troxerutin vinyl ester to the 1,2,3, 4-tetrahydroisoquinoline compound is 1: 1-12.

The ionic liquid consists of cations and anions, and the cations comprise pyridine cations

3-methylimidazolesCation(s)

Trioctylmethylammonium cation

(abbreviation TOMA)]⁺) Wherein R respectively represents ethyl, n-butyl, n-hexyl and n-octyl; the anion comprises BF₄ ^-、NO₃ ^-、PF₆ ^-、Tf₂N^-(bis (trifluoromethanesulfonylimide anion)), Br^-Or Cl^-。

The invention has the advantages that: the ionic liquid is used as a solvent and a reaction system of the catalyst, no additional catalyst is needed, the synthesis yield is high and reaches more than 70%, the reaction process is simple, the operation is simple and convenient, the reaction condition is mild, the post-treatment is easy, the ionic liquid is easy to recover, and the cost is low; meanwhile, the generated product has anti-tumor activity, has better inhibitory activity on colon cancer and breast cancer, and has better development and application values.

Detailed Description

The present invention is further illustrated by the following examples, but the content of the present invention is not intended to be limited to the examples.

Examples 1 to 1

Weighing 140mg (0.18mmol) of troxerutin, 138mg (0.75mmol) of glutaric acid divinyl ester and 10mL of pyridine in a 50mL conical flask, adding 120mg of subtilisin into the solution, placing the solution into a constant temperature oscillator at 50 ℃ for reaction, and rotating the speed to 250 rev.min^-1. After the reaction was completed for 72 hours, the enzyme was removed by filtration, and pyridine was distilled off under reduced pressure. Separating and purifying by column chromatography, eluting with ethyl acetate/methanol/water (15:3.6:0.5V/V) to obtain yellow solid troxerutin glutaryl vinyl ester 103mg (0.12mmol) with yield of 65%.

¹H-NMR(DMSO-d₆),δ(ppm)：12.49(s,1H,OH₅),7.85(s,1H,H_2’),7.74(d,1H,J＝7.2Hz,H_6’),7.22(dd,1H,J＝6.4Hz,J＝14.1Hz,-OCH＝),7.17(d,1H,J＝6.6Hz,H_5’),6.75(s,1H,H₈),6.38(s,1H,H₆),5.35(d,1H,J＝7.6Hz,H₁”),4.89(m,1H,OCH＝CH₂),4.65(m,1H,OCH＝CH₂),4.47(m,3H,2H of A acylated,1H of B acylated),4.32(m,1H,H₁”’),4.26(m,1H,H of B acylated),4.12-4.05(m,4H,H of A),3.75(m,4H,H of B),3.71-3.04(10H,Hof rhamnoglucosyl),2.47(m,2H,-CH₂-COOCH＝CH₂),2.26(m,2H,-CH₂-CO-troxerutin),1.80(m,2H,other CH₂of glutaridioyl part),0.97(d,3H,J＝6.2Hz,CH₃of rhamnosyl)；IR(KBr,cm^-1):3385(OH),1732(C＝O),1645(C＝C)；ESI-MS(m/z):905.1(M+Na)⁺.

Adding 95mg (0.11mmol) of troxerutin glutaryl vinyl ester, 73mg (0.66mmol) of phenethylamine and [ OMIM ] into a 50mL conical flask]BF₄10mL of (1-n-octyl-3-methylimidazolium tetrafluoroborate) is reacted for 24 hours under constant temperature oscillation at 50 ℃ in an air bath at 150 rpm. Extracting with ethyl acetate, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v), to obtain troxerutinamide derivative containing phenethylamine. 79.1mg of a pale yellow solid, yield 75%.

yellow powder,R_f＝0.21,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.82-7.83(m,1H,H_2’),7.67-7.73(m,1H,H_6’),7.10-7.24(m,6H,1H of H_5’,5H of phenethylamine),6.68(s,1H,H₈),6.36(s,1H,H₆),5.31-5.36(m,1H,H₁”),4.35-4.37(m,3H,2H of A acylated,1H ofB acylated),4.24-4.28(m,2H,1H of H₁”’,1H of B acylated),4.06-4.08(m,4H,H ofA),3.66-3.74(m,4H,H of B),3.01-3.74(m,12H,10H of rhamnoglucosyl,2H ofphenethylamine),2.63-2.67(t,J＝7.2Hz,2H,H of phenethylamine),2.04-2.26(m,4H,2H of CH₂COO-troxerutin,2H of CH₂CO-phenethylamine),1.67-1.71(m,2H,other CH₂ofglutaryl part),0.89-0.91(d,J＝6.0Hz,3H,CH3of rhamnosyl)；IR(KBr):3380cm^-1(OH),1732cm^-1(O＝C-O),1655cm^-1(O＝C-N),1454cm^-1(C-N)；ESI-MS(m/z):982.3(M+Na)⁺.

Examples 1 to 2

95mg (0.11mmol) of troxerutin glutaryl vinyl ester, 153mg (1.10mmol) of 4-fluorophenethylamine and 10mL of [ OMIM ] Br (1-n-octyl-3-methylimidazolium bromide) are added into a 50mL conical flask, and the mixture is subjected to constant temperature oscillation at 150rpm in an air bath at 50 ℃ for 24 hours of reaction. Extracting with ethyl acetate, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v), to obtain troxerutinamide derivative containing 4-fluorophenylethylamine. 91.4mg of a pale yellow solid, yield 85%.

yellow powder,R_f＝0.3,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.82-7.83(m,1H,H_2’),7.66-7.73(m,1H,H_6’),7.00-7.19(m,5H,1H of H_5’,5H of phenethylamine),6.66-6.68(m,1H,H₈),6.35-6.36(m,1H,H₆),5.32-5.37(m,1H,H₁”),4.35-4.38(m,3H,2H of Aacylated,1H of B acylated),4.24-4.28(m,2H,1H of H₁”_’,1H of B acylated),4.02-4.08(m,4H,H of A),3.67-3.76(m,4H,H of B),3.01-3.76(m,12H,10H ofrhamnoglucosyl,2H of phenethylamine),2.62-2.66(t,J＝7.0Hz,2H,H ofphenethylamine),2.04-2.56(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-phenethylamine),1.65-1.73(m,2H,other CH₂of glutaryl part),0.90-0.91(d,J＝6.0Hz,3H,CH₃of rhamnosyl)；IR(KBr):3334cm^-1(OH),1734cm^-1(O＝C-O),1655cm^-1(O＝C-N),1456cm^-1(C-N)；ESI-MS(m/z):1000.3(M+Na)⁺.

Examples 1 to 3

Weighing 140mg (0.18mmol) of troxerutin, 180mg (0.75mmol) of divinyl azelate and 10mL of pyridine as a solvent in a 50mL conical flask, adding 175mg of subtilisin, placing in a constant temperature oscillator at 60 ℃ for reaction, and rotating at 250rev min^-1. After the reaction time of 148h, the enzyme was removed by filtration and pyridine was distilled off under reduced pressure. The post-treatment was as above. This gave 101mg (0.10mmol) of troxerutin-nonanedioyl vinyl ester as a yellow solid in a yield of 57%.

¹H-NMR(DMSO-d₆),δ(ppm):12.50(s,1H,OH₅),7.85(s,1H,H_2’),7.75(d,1H,J＝8.4Hz,H_6’),7.21(dd,1H,J＝6.0Hz,J＝13.8Hz,-OCH＝),7.15(d,1H,J＝8.4Hz,H_5’),6.75(s,1H,H₈),6.38(s,1H,H₆),5.41(d,1H,J＝10.0Hz,H_1”),4.91(m,1H,OCH＝CH₂),4.61(m,1H,OCH＝CH₂),4.41(m,3H,2H of A acylated,1H of B acylated),4.32(m,1H,H_1”’),4.26(m,1H,H of B acylated),4.12-4.06(m,4H,H of A),3.75(m,4H,H of B),3.71-3.00(10H,Hof rhamnoglucosyl),2.39(t,2H,J＝7.2Hz,-CH₂-COOCH＝CH₂),2.34(t,2H,J＝7.2Hz,-CH₂-CO-troxerutin),1.52,1.25(m,10H,other CH₂of nonoanedioyl part),0.99(d,3H,J＝6.2Hz,CH₃of rhamnosyl)；IR(KBr,cm^-1):3377(OH),1735(C＝O),1647(C＝C)；ESI-MS(m/z):961.3(M+Na)⁺.

101.4mg (0.11mmol) of troxerutin-azelainyl ester, 123mg (0.88mmol) of 4-fluorophenethylamine and 10mL of [ BMIM ] Br (1-n-butyl-3-methylimidazolium bromide) are added into a 50mL conical flask, and the mixture is subjected to constant temperature oscillation at 150rpm in an air bath at 50 ℃ for 36 hours of reaction. Extracting with ethyl acetate, concentrating under reduced pressure, and separating and purifying by column chromatography, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v). 79.5mg of a pale yellow solid, yield 70%.

yellow powder,R_f＝0.32,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.81(s,1H,H_2’),7.63-7.70(m,1H,H_6’),6.97-7.17(m,6H,1H of H_5’,5H of phenethylamine),6.61(s,1H,H₈),6.32(s,1H,H₆),5.28-5.34(m,1H,H_1”),4.35-4.36(m,3H,2H of A acylated,1H of Bacylated),4.23-4.26(m,2H,1H of H_1”’,1H of B acylated),4.00-4.06(m,4H,H of A),3.67-3.75(m,4H,H of B),3.01-3.75(m,12H,10H of rhamnoglucosyl,2H ofphenethylamine),2.61-2.65(t,J＝6.6Hz,2H,H of phenethylamine),1.90-2.28(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-phenethylamine),1.01-1.45(m,10H,other CH₂ofazelaoyl part),0.89-0.91(d,J＝5.6Hz,3H,CH₃of rhamnosyl)；IR(KBr):3334cm^-1(OH),1732cm^-1(O＝C-O),1653cm^-1(O＝C-N),1456cm^-1(C-N)；ESI-MS(m/z):1056.4(M+Na)⁺.

Examples 1 to 4

95mg (0.11mmol) of troxerutin glutaryl vinyl ester, 117mg (1.10mmol) of benzylamine and 10mL of [ OPy ] Br (N-N-octyl pyridine bromide salt) are added into a 50mL conical flask, and the mixture is subjected to constant-temperature oscillation at 60 ℃ in an air bath at 150rpm and reacted for 24 hours. Extracting with ethyl acetate, concentrating under reduced pressure, separating and purifying by column chromatography, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v), and obtaining the troxerutinamide derivative containing benzylamine. 81.1mg of a pale yellow solid, yield 78%.

yellow powder,R_f＝0.29,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):¹H NMR(400MHz,DMSO-d₆,δppm):7.81(s,1H,H_2’),7.63-7.70(m,1H,H_6’),7.23-7.27(m,2H,H ofbenzylamine)7.16-7.18(m,3H,1H of H_5’,2H of benzylamine),7.07-7.09(m,1H,H ofbenzylamine),6.63(s,1H,H of H₈),6.32-6.33(d,J＝2.0Hz,1H,H₆),5.29-5.34(m,1H,H_1”),4.32-4.37(m,3H,2H of A acylated,1H of B acylated),4.20-4.26(m,4H,1H ofH_1”’,1H of B acylated,2H of benzylamine),4.02-4.05(m,4H,H of A),3.67-3.75(m,4H,H of B),3.01-3.75(m,10H,H of rhamnoglucosyl),2.09-2.34(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-benzylamine),1.73-1.80(m,2H,other CH₂of glutaryl part),0.88-0.90(d,J＝6.0Hz,3H,CH₃of rhamnosyl)；IR(KBr):3334cm^-1(OH),1732cm^-1(O＝C-O),1655cm^-1(O＝C-N),1456cm^-1(C-N)；ESI-MS(m/z):968.3(M+Na)⁺.

Examples 1 to 5

Adding 95mg (0.11mmol) of troxerutin glutaryl vinyl ester, 117mg (1.10mmol) of benzylamine and [ HMIM ] into a 50mL conical flask]BF₄10mL of (1-hexyl-3-methylimidazolium tetrafluoroborate) is reacted for 24 hours under constant temperature oscillation at 50 ℃ in an air bath at 150 rpm. The post-treatment was as above. Obtaining the troxerutinamide derivative containing benzylamine. 85.2mg of a pale yellow solid, 82% yield.

The data are as in examples 1-4.

Example 2-1

190mg (0.22mmol) of troxerutin glutaryl vinyl ester, 292.8mg (2.20mmol) of 1,2,3, 4-tetrahydroisoquinoline and 20mL of [ OMIM ] Br are added into a 50mL conical flask, and the mixture is shaken in an air bath shaker at 60 ℃ at constant temperature of 150rpm and reacted for 24 h. Extracting with ethyl acetate, rotary evaporating under reduced pressure, removing most of organic solvent, and separating by column chromatography to obtain the product, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v). Obtaining the troxerutin amide derivative containing tetrahydroisoquinoline. The product was 160mg as a pale yellow solid with a yield of 75%.

yellow solid,R_f＝0.1,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.81-7.83(m,1H,H_2’),7.67-7.72(m,1H,H_6’),7.08-7.12(m,5H,1H of H_5’,4H oftetrahydroisoquinoline),6.69(s,1H,H₈),6.36(s,1H,H₆),5.33-5.37(m,1H,H_1”),4.52-4.53(m,2H,H of tetrahydroisoquinoline),4.34-4.43(m,3H,2H of A acylated,1H ofB acylated),4.24-4.28(m,2H,1H of H_1”’,1H of B acylated),4.02-4.08(m,4H,H ofA),3.70-3.78(m,4H,H of B),3.54-3.60(m,2H,H of tetrahydroisoquinoline),3.01-3.67(m,10H,H of rhamnoglucosyl),2.71-2.75(m,2H,H of tetrahydroisoquinoline),2.36-2.40(m,4H,2H of CH₂COO-troxerutin,2H of CH₂CO-tetrahydroisoquinoline),1.73-1.78(m,2H,other CH₂of glutaryl part),0.90-0.91(d,J＝4.8Hz,3H,CH₃ofrhamnosyl)；¹³C NMR(DMSO-d₆):177.9(C-4),173.3(C＝O),171.0(C＝O),165.1(C-7),161.3(C-9),156.9(C-5),151.4(C-2),150.7(C-4’),147.4(C-3’),135.2(tetrahydroisoquinoline),134.2(tetrahydroisoquinoline),133.7(C-3),128.9(tetrahydroisoquinoline),128.8(tetrahydroisoquinoline),126.8(tetrahydroisoquinoline),126.6(tetrahydroisoquinoline),123.3(C-1’),122.7(C-6’),115.3(C-5’),113.4(C-2’),105.5(C-10),101.7(C-1”),101.4(C-1”’),98.8(C-6),93.3(C-8),76.8(C-3”),76.4(C-5”),74.6(C-2”),72.2(C-4”’),71.1(C-3”’),71.0(C-2”’),70.9(C-4”),70.8(C-A),70.6(C-A),68.7(C-5”’),67.4(C-6”),67.2(C-A),62.8(C-B),60.0(C-B),59.7(C-B),46.7(tetrahydroisoquinoline),43.9(tetrahydroisoquinoline),42.9(tetrahydroisoquinoline),33.3((CH₂)_n),32.3((CH₂)_n),29.2((CH₂)_n),18.2(C-6”’)；IR(KBr):3369cm^-1(OH),1732cm^-1(O＝C-O),1655cm^-1(O＝C-N),1452cm^-1(C-N)；ESI-MS(m/z):995(M+Na)⁺.

Examples 2 to 2

Weighing 140mg (0.18mmol) of troxerutin, 172mg (0.75mmol) of divinyl dodecanedioate and 10mL of pyridine as a solvent in a 50mL conical flask, adding 120mg of subtilisin, placing in a constant temperature oscillator at 50 ℃ for reaction, and rotating at 250rev min^-1. After the reaction for 96 hours, the enzyme was removed by filtration and pyridine was distilled off under reduced pressure. Column chromatography was performed using ethyl acetate/methanol/water (15:3.6:0.5V/V) as eluent to give 89mg (0.092mmol) of troxerutin dodecavinylester as a yellow solid in 51% yield.

Yellow powder，,R_f0.34；¹H-NMR(DMSO-d₆),δ(ppm):12.50(s,1H,OH₅),7.85(s,1H,H_2’),7.74(d,1H,J＝8.7Hz,H_6’),7.22(dd,1H,J＝6.2Hz,J＝14.0Hz,-OCH＝),7.15(d,1H,J＝8.8Hz,H_5’),6.75(s,1H,H₈),6.38(s,1H,H₆),5.38(d,1H,J＝6.0Hz,H_1”),4.92(m,1H,OCH＝CH₂),4.60(m,1H,OCH＝CH₂),4.42(m,3H,2H of A acylated,1H of B acylated),4.32(m,1H,H_1”’),4.26(m,1H,H of B acylated),4.13-4.06(m,4H,H of A),3.75(m,4H,Hof B),3.70-3.04(10H,H of rhamnoglucosyl),2.41(m,2H,-CH₂-COOCH＝CH₂),2.33(m,2H,-CH₂-CO-troxerutin),1.52,1.21(m,16H,other CH₂of tridecanoyl part),0.96(d,3H,J＝6.2Hz,CH₃of rhamnosyl)；IR(KBr,cm^-1):3392(OH),1735(C＝O),1647(C＝C)；ESI-MS(m/z):1003.3(M+Na)⁺.

In a 50mL conical flask were added 212.3mg (0.22mmol) of troxerutin dodecavinylester, 176mg (1.32mmol) of 1,2,3, 4-tetrahydroisoquinoline, [ OMIM ]]NO₃20mL of the reaction solution was stirred in an air bath shaker at 60 ℃ at a constant temperature of 150rpm, and the reaction was carried out for 48 hours. Extracting with ethyl acetate, rotary steaming under reduced pressure to remove most of organic solventSeparating by column chromatography to obtain product, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v). The product was 176mg as a pale yellow solid with a yield of 75%.

yellow solid,R_f＝0.23,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.87(s,1H,H_2’),7.72-7.79(m,1H,H_6’),7.13-7.18(m,5H,1H of H_5’,4H of tetrahydroisoquinoline),6.72(s,1H,H₈),6.39(s,1H,H₆),5.36-5.41(m,1H,H_1”),4.58-4.62(m,2H,H oftetrahydroisoquinoline),4.35-4.44(m,3H,2H of A acylated,1H of B acylated),4.28-4.32(m,2H,1H of H_1”’,1H of B acylated),4.07-4.12(m,4H,H of A),3.74-3.82(m,4H,H of B),3.63-3.66(m,2H,H of tetrahydroisoquinoline),3.05-3.73(m,10H,Hof rhamnoglucosyl),2.75-2.84(m,2H,H of tetrahydroisoquinoline),2.29-2.36(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-tetrahydroisoquinoline),1.16-1.49(m,16H,other CH₂of dodecanoyl part),0.95-0.96(d,J＝6Hz,3H,CH₃of rhamnosyl)；¹³C NMR(DMSO-d₆):177.8(C-4),173.8(C＝O),172.2(C＝O),165.0(C-7),160.8(C-9),156.8(C-5),151.4(C-2),150.7(C-4’),147.8(C-3’),135.1(tetrahydroisoquinoline),134.2(tetrahydroisoquinoline),133.6(C-3),128.8(tetrahydroisoquinoline),127.0(tetrahydroisoquinoline),126.8(tetrahydroisoquinoline),126.6(tetrahydroisoquinoline),123.7(C-1’),122.6(C-6’),115.4(C-5’),114.9(C-2’),105.3(C-10),101.9(C-1”),101.2(C-1”’),98.7(C-6),93.3(C-8),76.5(C-3”),76.1(C-5”),74.3(C-2”),72.0(C-4”’),70.8(C-3”’),70.7(C-2”’),70.6(C-4”),70.5(C-A),70.4(C-A),68.6(C-5”’),67.5(C-6”),67.4(C-A),62.9(C-B),59.8(C-B),59.6(C-B),47.1(tetrahydroisoquinoline),44.0(tetrahydroisoquinoline),43.2(tetrahydroisoquinoline),33.9((CH₂)_n),33.2((CH₂)_n),32.9((CH₂)_n),31.1((CH₂)_n),29.2((CH₂)_n),29.0((CH₂)_n),28.8((CH₂)_n),28.2((CH₂)_n),25.1((CH₂)_n),24.7((CH₂)_n),17.9(C-6”’)；IR(KBr):3369cm^-1(OH),1732cm^-1(O＝C-O),1653cm^-1(O＝C-N),1456cm^-1(C-N)；ESI-MS(m/z):1092.8(M+Na)⁺.

Examples 2 to 3

Weighing 140mg (0.18mmol) of troxerutin, 172mg (0.75mmol) of divinyl adipate and 10mL of pyridine as a solvent in a 50mL conical flask, adding 120mg of subtilisin into the solution, placing the solution into a constant temperature oscillator at 55 ℃ for reaction, and rotating at 250 rev.min^-1. After the reaction for 96 hours, the enzyme was removed by filtration and pyridine was distilled off under reduced pressure. Column chromatography was performed with ethyl acetate/methanol/water (15:3.6:0.5V/V) as eluent to give troxerutin adipyl ester 96.8mg (0.108mmol) as a yellow solid in 60% yield.

Yellow powder,R_f0.32；¹H-NMR(DMSO-d₆),δ(ppm):12.49(s,1H,OH₅),7.84(s,1H,H_2’),7.73(d,1H,J＝7.2Hz,H_6’),7.20(dd,1H,J＝6.24Hz,J＝14.0Hz,-OCH＝),7.14(d,1H,J＝7.6Hz,H_5’),6.73(s,1H,H₈),6.38(s,1H,H₆),5.34(d,1H,J＝7.3Hz,H_1”),4.89(m,1H,OCH＝CH₂),4.64(m,1H,OCH＝CH₂),4.40(m,3H,2H of A acylated,1H of B acylated),4.31(m,1H,H_1”’),4.26(m,1H,H of B acylated),4.12-4.06(m,4H,H of A),3.74(m,4H,Hof B),3.7-3.1(10H,H of rhamnoglucosyl),2.44(m,2H,-CH₂-COOCH＝CH₂),2.38(m,2H,-CH₂-CO-troxerutin),1.58(m,4H,other CH₂of hexanedioyl part),0.99(d,3H,J＝6.2Hz,CH₃of rhamnosyl)；IR(KBr,cm^-1):3412(OH),1726(C＝O),1648(C＝C)；ESI-MS(m/z):919.1(M+Na)⁺.

In a 50mL conical flask were added 193mg (0.22mmol) of troxerutin adipamide, 424.8mg (2.20mmol) of 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline, [ OPy ]]BF₄20mL of the solution was reacted for 24 hours with shaking at a constant temperature of 150rpm in an air bath shaker at 60 ℃. Extracting with ethyl acetate, rotary evaporating under reduced pressure, removing most of organic solvent, separating by column chromatography to obtain product, and eluting with ethyl acetate/methanol/water (20/3/1, v/v). Obtaining the troxerutin amide derivative containing the bisdimethoxytetrahydroisoquinoline. The product was 165.5mg as a pale yellow solid, in 72% yield.

yellow solid,R_f＝0.15,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.82-7.84(m,1H,H_2’),7.66-7.72(m,1H,H_6’),7.09-7.12(m,1H,H_5’),6.67-6.71(m,3H,1H of H₈,2H oftetrahydroisoquinoline),6.35(s,1H,H₆),5.32-5.37(m,1H,H_1”),4.43-4.47(m,2H,H oftetrahydroisoquinoline),4.32-4.37(m,3H,2H of A acylated,1H of B acylated),4.23-4.28(m,2H,1H of H_1”’,1H of B acylated),4.02-4.08(m,4H,H of A),3.72-3.73(m,4H,H of B),3.65-3.66(m,6H,H of tetrahydroisoquinoline-OCH ₃),3.53-3.57(m,2H,H of tetrahydroisoquinoline),3.00-3.66(m,10H,H of rhamnoglucosyl),2.60-2.68(m,2H,H of tetrahydroisoquinoline),2.29-2.38(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-tetrahydroisoquinoline),1.43-1.58(m,4H,other CH₂of hexanadioylpart),0.90-0.91(d,J＝6.0Hz,3H,CH₃of rhamnosyl)；¹³C NMR(DMSO-d₆):177.9(C-4),173.4(C＝O),171.2(C＝O),165.1(C-7),161.3(C-9),156.9(C-5),151.5(C-2),150.8(C-4’),148.1(tetrahydroisoquinoline),147.7(tetrahydroisoquinoline),147.5(C-3’),134.2(C-3),126.9(tetrahydroisoquinoline),125.8(tetrahydroisoquinoline),123.4(C-1’),122.8(C-6’),115.5(C-5’),113.8(C-2’),112.2(tetrahydroisoquinoline),110.4(tetrahydroisoquinoline),105.5(C-10),101.9(C-1”),101.4(C-1”’),98.9(C-6),93.3(C-8),76.8(C-3”),76.4(C-5”),74.6(C-2”),72.2(C-4”’),71.1(C-3”’),70.9(C-2”’),70.8(C-4”),70.8(C-A),70.6(C-A),68.7(C-5”’),67.4(C-6”),67.2(C-A),62.8(C-B),60.0(C-B),59.8(C-B),55.9(-OCH₃),46.6(tetrahydroisoquinoline),43.7(tetrahydroisoquinoline),43.1(tetrahydroisoquinoline),33.7((CH₂)_n),32.5((CH₂)_n),28.8((CH₂)_n),27.9((CH₂)_n),18.1(C-6”’)；IR(KBr):3367cm^-1(OH),1732cm^-1(O＝C-O),1653cm^-1(O＝C-N),1452cm^-1(C-N)；ESI-MS(m/z):1069(M+Na)⁺.

Examples 2 to 4

Weighing 282mg (0.38mmol) of troxerutin, 378mg (1.5mmol) of divinyl sebacate and 10mL of pyridine as solvents in a 50mL conical flask, adding 300mg of subtilisin, placing in a constant temperature oscillator at 60 ℃ for reaction, and rotating at 250rev min^-1. After the reaction was completed for 120 hours, the enzyme was removed by filtration, and pyridine was distilled off under reduced pressure. Purification was as above. Yellow solid troxerutin-sebacoyl vinyl ester 200mg (0.21mmol) is obtained in 55% yield.

¹H-NMR(DMSO-d₆),δ(ppm):12.49(s,1H,OH₅),7.84(s,1H,H_2’),7.72(d,1H,J＝7.0Hz,H_6’),7.20(dd,1H,J＝6.21Hz,J＝14.0Hz,-OCH＝),7.14(d,1H,J＝7.4Hz,H_5’),6.73(s,1H,H₈),6.38(s,1H,H₆),5.34(d,1H,J＝7.3Hz,H_1”),4.89(m,1H,OCH＝CH₂),4.63(m,1H,OCH＝CH₂),4.39(m,3H,2H of A acylated,1H of B acylated),4.31(m,1H,H_1”’),4.26(m,1H,H of B acylated),4.12-4.06(m,4H,H of A),3.74(m,4H,H of B),3.7-3.1(10H,H ofrhamnoglucosyl),2.40(t,2H,J＝7.2Hz,-CH₂-COOCH＝CH₂),2.33(t,2H,J＝6.9Hz,-CH₂-CO-troxerutin),1.58,1.22(m,12H,other CH₂of decanedioyl part),0.99(d,3H,J＝6.2Hz,CH₃of rhamnosyl)；IR(KBr,cm^-1):3410(OH),1728(C＝O),1649(C＝C)；ESI-MS(m/z):975.2(M+Na)⁺.

To a 50mL Erlenmeyer flask were added 209mg (0.22mmol) of troxerutin sebacoyl vinyl ester, 424.8mg (2.20mmol) of 6, 7-dimethoxy-1, 2,3, 4-tetrahydroisoquinoline, and 20mL of [ BPy ] Cl (N-N-butylpyridinium chloride), followed by reaction at constant temperature of 150rpm in an air bath shaker at 70 ℃ for 36 hours. Extracting with ethyl acetate, rotary evaporating under reduced pressure, removing most of organic solvent, and separating by column chromatography to obtain the product, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v). The product was 181.3mg as a pale yellow solid, in 75% yield.

yellow solid,R_f＝0.2,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):7.83(s,1H,H_2’),7.67-7.74(m,1H,H_6’),7.09-7.13(s,1H,H_5’),6.68-6.73(m,3H,1H of H₈,2H oftetrahydroisoquinoline),6.35(s,1H,H₆),5.32-5.38(m,1H,H_1”),4.43-4.48(m,2H,H oftetrahydroisoquinolined),4.35-4.37(m,3H,2H of A acylated,1H of B acylated),4.24-4.28(m,2H,1H of H_1”’,1H of B acylated),4.03-4.08(m,4H,H of A),3.71-3.73(m,4H,H of B),3.67-3.68(m,6H,H of tetrahydroisoquinoline-OCH ₃),3.53-3.58(m,2H,H of tetrahydroisoquinoline),3.01-3.68(m,10H,H of rhamnoglucosyl),2.61-2.70(m,2H,H of tetrahydroisoquinoline),2.26-2.33(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-tetrahydroisoquinoline),1.12-1.46(m,12H,other CH₂of decanedioylpart),0.91-0.92(d,J＝6.0Hz,3H,CH₃of rhamnosyl)；¹³C NMR(DMSO-d₆):177.9(C-4),173.4(C＝O),171.5(C＝O),165.1(C-7),161.3(C-9),156.9(C-5),151.5(C-2),150.8(C-4’),147.8(tetrahydroisoquinoline),147.7(tetrahydroisoquinoline),147.5(C-3’),134.3(C-3),126.9(tetrahydroisoquinoline),125.8(tetrahydroisoquinoline),123.7(C-1’),123.0(C-6’),115.5(C-5’),113.5(C-2’),112.2(tetrahydroisoquinoline),110.4(tetrahydroisoquinoline),105.5(C-10),101.9(C-1”),101.3(C-1”’),98.9(C-6),93.3(C-8),76.9(C-3”),76.4(C-5”),74.6(C-2”),72.2(C-4”’),71.1(C-3”’),70.9(C-2”’),70.8(C-4”),70.6(C-A),70.6(C-A),68.7(C-5”’),67.5(C-6”),67.2(C-A),62.8(C-B),60.0(C-B),59.8(C-B),56.0(-OCH₃),46.7(tetrahydroisoquinoline),43.7(tetrahydroisoquinoline),43.2(tetrahydroisoquinoline),33.9((CH₂)_n),32.9((CH₂)_n),29.2((CH₂)_n),29.1((CH₂)_n),28.9((CH₂)_n),27.9((CH₂)_n),25.2((CH₂)_n),24.9((CH₂)_n),18.1(C-6”’)；IR(KBr):3369cm^-1(OH),1730cm^-1(O＝C-O),1653cm^-1(O＝C-N),1452cm^-1(C-N)；ESI-MS(m/z):1125(M+Na)⁺.

Examples 2 to 5

In a 50mL conical flask, 190mg (0.22mmol) of troxerutin glutaryl vinyl ester, 359mg (2.20mmol) of 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline, and [ TOMA ] are added][Tf₂N]20mL of (N-hexylpyridine bistrifluoromethanesulfonylimide salt), and reacting for 30 hours in an air bath shaker at 60 ℃ with constant temperature shaking at 150 rpm. Extracting with ethyl acetate, concentrating the extractive solution, separating by column chromatography to obtain product, and eluting with ethyl acetate/methanol/water (20/3/1, v/v) to obtain troxerutinamide derivative containing methoxytetrahydroisoquinoline. 155mg of a pale yellow solid product, yield 71%.

yellow solid,R_f＝0.13,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):¹H NMR(400MHz,DMSO-d₆,δppm):7.81-7.83(m,1H,H_2’),7.65-7.71(m,1H,H_6’),7.00-7.10(m,2H,1H of H_5’,1H of tetrahydroisoquinoline),6.61-6.74(m,3H,1H of H₈,2H oftetrahydroisoquinoline),6.34(s,1H,H₆),5.32-5.38(m,1H,H_1”),4.41-4.54(m,2H,H oftetrahydroisoquinoline),4.31-4.41(m,3H,2Hof A acylated,1H of B acylated),4.23-4.28(m,2H,1H of H_1”’,1H of B acylated),3.99-4.13(m,4H,H of A),3.68-3.82(m,4H,H of B),3.59-3.68(m,3H,H of tetrahydroisoquinoline-OCH ₃),3.48-3.59(m,2H,H of tetrahydroisoquinoline),2.96-3.73(m,10H,H of rhamnoglucosyl),2.66-2.76(m,2H,H of tetrahydroisoquinoline),2.25-2.45(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-tetrahydroisoquinoline),1.66-1.86(m,2H,other CH₂of glutaryl part),0.90(s,3H,CH₃of rhamnosyl)；¹³C NMR(DMSO-d₆):177.9(C-4),173.3(C＝O),170.9(C＝O),165.1(C-7),161.3(C-9),158.1(tetrahydroisoquinoline),156.9(C-5),151.5(C-2),150.8(C-4’),147.5(C-3’),136.3(tetrahydroisoquinoline),134.2(C-3),127.9(tetrahydroisoquinoline),126.1(tetrahydroisoquinoline),123.4(C-1’),122.8(C-6’),115.4(C-5’),113.7(C-2’),113.4(tetrahydroisoquinoline),112.9(tetrahydroisoquinoline),105.5(C-10),101.9(C-1”),101.3(C-1”’),98.8(C-6),93.3(C-8),76.8(C-3”),76.4(C-5”),74.6(C-2”),72.2(C-4”’),71.1(C-3”’),71.0(C-2”’),70.8(C-4”),70.6(C-A),70.6(C-A),68.7(C-5”’),67.4(C-6”),67.2(C-A),62.8(C-B),60.0(C-B),59.7(C-B),55.4(-OCH₃),46.2(tetrahydroisoquinoline),43.4(tetrahydroisoquinoline),42.8(tetrahydroisoquinoline),33.3((CH₂)_n),32.0((CH₂)_n),29.5((CH₂)_n),18.2(C-6”’)；IR(KBr):3367cm^-1(OH),1728cm^-1(O＝C-O),1653cm^-1(O＝C-N),1455cm^-1(C-N)；ESI-MS(m/z):1024.8(M+Na)⁺.

Examples 2 to 6

In a 50mL conical flask, 202.8mg (0.22mmol) of troxerutin nonane diacyl vinyl ester, 359mg (2.20mmol) of 6-methoxy-1, 2,3, 4-tetrahydroisoquinoline, and HPy]BF₄20mL of (N-N-hexylpyridinium tetrafluoroborate), and reacting for 36h in an air bath oscillator at 60 ℃ under constant temperature oscillation at 150 rpm. Extracting with ethyl acetate, concentrating the extractive solution, and separating by column chromatography to obtain the product, wherein the eluent is ethyl acetate/methanol/water (20/3/1, v/v). 170mg of a pale yellow solid product, 73% yield.

yellow solid,R_f＝0.18,¹H NMR(400MHz,DMSO-d₆+D₂O,δppm):¹H NMR(400MHz,DMSO-d₆,δppm):7.82(s,1H,H_2’),7.64-7.71(m,1H,H_6’),6.99-7.09(m,2H,1H of H_5’,1H oftetrahydroisoquinoline),6.64-6.71(m,3H,1H of H₈,2H oftetrahydroisoquinoline),6.33(s,1H,H₆),5.30-5.35(m,1H,H_1”),4.41-4.45(m,2H,H oftetrahydroisoquinoline),4.32-4.40(m,3H,2H of A acylated,1H of B acylated),4.20-4.29(m,2H,1H of H_1”’,1H of B acylated),4.04-4.10(m,4H,H of A),3.68-3.80(m,4H,H of B),3.62-3.68(m,3H,H of tetrahydroisoquinoline-OCH ₃),3.48-3.59(m,2H,H of tetrahydroisoquinoline),2.99-3.66(m,10H,H of rhamnoglucosyl),2.62-2.77(m,2H,H of tetrahydroisoquinoline),2.22-2.26(m,4H,2H of CH₂CO-troxerutin,2H of CH₂CO-tetrahydroisoquinoline),1.02-1.52(m,10H,other CH₂of azelaoylpart),0.89-0.91(d,J＝5.9Hz,3H,CH₃of rhamnosyl)；¹³C NMR(DMSO-d₆):177.9(C-4),173.4(C＝O),171.5(C＝O),165.1(C-7),161.3(C-9),158.1(tetrahydroisoquinoline),156.9(C-5),151.5(C-2),150.8(C-4’),147.5(C-3’),136.3(tetrahydroisoquinoline),134.2(C-3),127.8(tetrahydroisoquinoline),126.2(tetrahydroisoquinoline),123.7(C-1’),122.8(C-6’),115.4(C-5’),113.5(C-2’),113.5(tetrahydroisoquinoline),112.9(tetrahydroisoquinoline),105.5(C-10),101.9(C-1”),101.3(C-1”’),98.8(C-6),93.3(C-8),76.8(C-3”),76.4(C-5”),74.6(C-2”),72.2(C-4”’),71.1(C-3”’),70.9(C-2”’),70.8(C-4”),70.6(C-A),70.6(C-A),68.7(C-5”’),67.4(C-6”),67.2(C-A),62.8(C-B),60.0(C-B),59.8(C-B),55.4(-OCH₃),46.4(tetrahydroisoquinoline),43.4(tetrahydroisoquinoline),42.9(tetrahydroisoquinoline),33.8((CH₂)_n),32.9((CH₂)_n),29.6((CH₂)_n),29.0((CH₂)_n),28.8((CH₂)_n),25.2((CH₂)_n),24.8((CH₂)_n),18.2(C-6”’)；IR(KBr):3369cm^-1(OH),1730cm^-1(O＝C-O),1655cm^-1(O＝C-N),1452cm^-1(C-N)；ESI-MS(m/z):1080.8(M+Na)⁺.

And (3) biological activity test: the MTT method is adopted to measure the cytotoxic activity of troxerutin and compounds (I) and (II) on HT-29 (human colon cancer cells) and MCF-7 (human breast cancer cells).

Some of the test results are given in the following table:

the data show that the compounds (I) and (II) have obvious inhibiting effect on HT-29 and MCF-7, are superior to troxerutin, and can be developed as potential medicaments for resisting colon cancer and breast cancer.

Claims (5)

1. The troxerutin amide derivative is characterized by being an N- (4-fluoro) phenethyl/benzyl troxerutin amide derivative, and having the following structural formula:

n is 2,3,4,5,6,7,8,10, 11.

2. The troxerutin amide derivative according to claim 1, which is selected from the following compounds:

(1)

n is 3,4,5, 7

(2)

n is 3,4,5

(3)

n is 3,4, 5.

3. A process for the preparation of troxerutin amide derivatives as claimed in claim 1, by the steps of:

troxerutin and fatty acid divinyl ester react at 40-60 ℃ by taking pyridine as a reaction medium under the catalysis of subtilisin, and the troxerutin vinyl ester shown in the formula A is obtained by column separation after the reaction is finished;

in ionic liquid, reacting troxerutin vinyl esters with different chain lengths in a formula A with phenethylamine, 4-fluoro-phenethylamine or benzylamine compounds at 40-70 ℃; after the reaction is finished, extracting by using an organic solvent, concentrating the extract under reduced pressure, and separating by using column chromatography to obtain the derivative shown in the general formula (I);

the ionic liquid consists of a cation and an anion, the cation being selected from

Wherein R respectively represents ethyl, n-butyl, n-hexyl or n-octyl; the anion is selected from BF₄ ^-、NO₃ ^-、PF₆ ^-、Tf₂N^-、Br^-Or Cl^-；

The fatty acid divinyl ester has the following structural formula: CH (CH)₂＝CHOOC(CH₂)nCOOCH＝CH₂And n is 2,3,4,5,6,7,8,10, 11.

4. The method for preparing the troxerutin amide derivative with the structural formula II is characterized by comprising the following steps of:

n is 2,3,4,5,6,7,8,10, 11; r₁And R₂Are respectively-H, -OCH₃The same or different;

troxerutin and fatty acid divinyl ester react at 40-60 ℃ by taking pyridine as a reaction medium under the catalysis of subtilisin, and the troxerutin vinyl ester shown in the formula A is obtained by column separation after the reaction is finished;

ionic liquid as reaction medium, troxerutin vinyl ester of formula A and

reacting a reaction substrate at 40-70 DEG C(ii) a After the reaction is finished, extracting the product by an organic solvent, concentrating, and separating by column chromatography to obtain the tetrahydroisoquinoline troxerutin amide derivative (II);

the ionic liquid consists of a cation and an anion, the cation being selected from

Wherein R respectively represents ethyl, n-butyl, n-hexyl or n-octyl; the anion is selected from BF₄ ^-、NO₃ ^-、PF₆ ^-、Tf₂N^-、Br^-Or Cl^-；

The fatty acid divinyl ester has the following structural formula: CH (CH)₂＝CHOOC(CH₂)nCOOCH＝CH₂And n is 2,3,4,5,6,7,8,10, 11.

5. The use of a troxerutinamide derivative as claimed in any of claims 1-2 in the manufacture of a medicament, wherein the troxerutinamide derivative is used as an active ingredient in the manufacture of a medicament against colon cancer or breast cancer.