Cyclic hydrocarbon chrysin derivative and preparation method thereof

Abstract

The invention provides a chrysin derivative as well as a preparation method and application thereof. The preparation method of the chrysin derivative comprises the following steps: S1, reacting a mixed solution containing a solvent I, chrysin and an acyl chloride compound to obtain a reaction product containing the chrysin derivative; and optionally, S2, carrying out separation and purification treatment on the reaction product, so as to obtain the separated and purified chrysin derivative. According to the preparation method of the chrysin derivative provided by the invention, the yield of the prepared chrysin derivative is high (the highest yield can reach 98%).

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and relates to a cyclic hydrocarbon chrysin derivative and a preparation method thereof, as well as a pharmaceutical composition and application of the derivative in preparing anti-inflammatory or anti-tumor drugs. Background Art

[0002] Chrysin is a natural flavonoid product with a wide range of applications, such as antioxidants and pharmacological activities. However, chrysin itself has poor solubility and needs to be modified to enhance its solubility and improve its physical and chemical properties to expand its application range. Although there have been many reports on the structural modification of chrysin, such as the introduction of alkanes, amino acids and alcohol compounds, there have been no reports on the introduction of cyclic hydrocarbon compounds into the chrysin skeleton. Summary of the invention

[0003] In view of the above background, the purpose of the present invention is to solve at least one of the deficiencies of the prior art. For example, one of the purposes of the present invention is to provide a cyclic hydrocarbon chrysin derivative, in which a cyclic group of a cycloalkyl group, a heterocycloalkyl group, an aromatic group or a heteroaromatic group is introduced into the chrysin skeleton; for another example, another purpose of the present invention is to provide a method for preparing a cyclic hydrocarbon chrysin derivative, which can be prepared in one step reaction, and the prepared chrysin derivative has good purity and high yield.

[0004] In order to achieve the above-mentioned object, the first aspect of the present invention provides a cyclic hydrocarbon chrysin derivative having a structure shown in formula (I):

[0005]

[0006] In formula (I):

[0007] R1 is selected from substituted or unsubstituted cycloalkyl I, substituted or unsubstituted heterocycloalkyl I, substituted or unsubstituted aryl I and substituted or unsubstituted heteroaryl I;

[0008] R2 is selected from hydroxyl or a group represented by formula (II), wherein R3 is selected from substituted or unsubstituted cycloalkyl II, substituted or unsubstituted heterocycloalkyl II, substituted or unsubstituted aromatic II and substituted or unsubstituted heteroaromatic II; the dotted bond indicates the connection position;

[0009]

[0010] In R1 and R3, the substituents on the substituted cycloalkyl I, substituted cycloalkyl II, substituted heterocycloalkyl I, substituted heterocycloalkyl II, substituted aromatic I, substituted aromatic II, substituted heteroaromatic I and substituted heteroaromatic II are selected from C1-C20 straight-chain alkyl, C3-C20 branched-chain alkyl, C1-C20 alkoxy and mono-substituted or di-substituted amino;

[0011] The heterocycloalkyl group I has 5-10 ring-forming atoms I, wherein at least one skeleton ring-forming atom I is O, N, S or P;

[0012] The heterocycloalkyl group II has 5-10 skeleton ring atoms II, wherein at least one skeleton ring atom II is O, N, S or P;

[0013] The heteroaromatic group I has 5 to 10 skeleton ring atoms III, wherein at least one skeleton ring atom III is O, N, S or P;

[0014] The heteroaromatic group II has 5 to 10 skeleton ring atoms IV, wherein at least one skeleton ring atom IV is O, N, S or P.

[0015] In some embodiments of the present invention, the cycloalkyl group I and cycloalkyl group II are independently selected from one of C3 to C20 cycloalkyl groups.

[0016] In some embodiments of the present invention, the heterocycloalkyl group I and the heterocycloalkyl group II are independently selected from one of furanyl, tetrahydrofuranyl, piperidinyl, pyridinyl and bipyridinyl.

[0017] In some embodiments of the present invention, the heteroaromatic group I and the heteroaromatic group II are independently selected from one of pyridyl, pyrimidinyl, thienyl, pyrazolyl and furanyl.

[0018] In some embodiments of the present invention, the aromatic group I and the aromatic group II are independently selected from a monocyclic aromatic group or a condensed-ring aromatic group, preferably a benzyl group or a naphthyl group.

[0019] In order to achieve the above object, the second aspect of the present invention provides a method for preparing a chrysin derivative, comprising the steps of:

[0020] S1, reacting a mixed solution containing solvent I, chrysin and an acyl chloride compound to obtain a reaction product containing the chrysin derivative; and

[0021] Optionally, S2, separating and purifying the reaction product to obtain the separated and purified chrysin derivative.

[0022] Wherein, the acyl chloride compound is selected from one or two of the compounds represented by formula (III),

[0023]

[0024] When the acyl chloride compound is one, R1 in Formula I is R, and R2 is OH;

[0025] When there are two types of acyl chloride compounds, they are In formula I, R1 is R' and R2 is R".

[0026] In the present invention, when the acyl chloride compound is one, R in formula (III) has the same definition as R1 in formula I.

[0027] In the present invention, when there are two types of acyl chloride compounds, R' in Formula I has the same definition as R1, The R" in Formula I has the same definition as R2 in Formula I.

[0028] In the present invention, the reaction in step S1 can be carried out in a reaction vessel such as a round-bottom flask.

[0029] In some embodiments of the present invention, in step S1, the molar ratio of chrysin to the acyl chloride compound in the mixed solution is 1:10-1; preferably 1:1-3.

[0030] In some embodiments of the present invention, in step S1, the solvent I is selected from at least one of acetone, tetrahydrofuran, dioxane and chloroform.

[0031] In some embodiments of the present invention, the mixed solution in step S1 further comprises an acid-binding agent, and the molar ratio of the chrysin to the acid-binding agent is 1:10-1; preferably 1:4-6.

[0032] In some embodiments of the present invention, the acid binding agent is selected from at least one of organic bases; more preferably selected from at least one of triethylamine, pyridine, picoline, N,N-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dioxydimethyl ether acetate (DMA) and N-methylpyrrolidone (NMP).

[0033] In some embodiments of the present invention, the reaction conditions in step S1 include: a temperature of 0° C. to 120° C.; and / or a reaction time of 0.5 to 3 h, preferably 1.5 to 2 h.

[0034] According to the present invention, after the reaction in step S1 is completed, water (such as distilled water) may be added to terminate the reaction.

[0035] In some embodiments of the present invention, step S1 comprises:

[0036] S101, obtaining a mixed solution I containing the chrysin and the solvent I;

[0037] S102, mixing the first solution containing the acyl chloride compound and the solvent II with the mixed solution I to obtain a mixed solution II containing the chrysin derivative;

[0038] S103, mixing the second solution containing the acid binding agent and the solvent III with the mixed solution II to obtain a reaction product containing the chrysin derivative.

[0039] In some embodiments of the present invention, in step S102, the solvent II is at least one of acetone, tetrahydrofuran, dioxane and chloroform.

[0040] In some embodiments of the present invention, in step S102, the first solution is added dropwise to the mixed solution I to obtain the mixed solution II; preferably, the dropping speed is 1 drop / second.

[0041] In some embodiments of the present invention, in step S103, the solvent III is at least one of acetone, tetrahydrofuran, dioxane and chloroform.

[0042] In the present invention, solvent I, solvent II and solvent III are the same or different, and are independently selected from at least one of acetone, tetrahydrofuran, dioxane and chloroform. The present invention has no strict limitation on the amount of solvent I, solvent II and solvent III, and those skilled in the art can determine it according to the specific situation.

[0043] In some embodiments of the present invention, in step S103, the second solution is added dropwise to the mixed solution II to obtain the mixed solution III; preferably, the dropping speed is 1 drop / second.

[0044] In the present invention, the first solution and the second solution may be added dropwise using a constant pressure dropping funnel. In the present invention, in steps S102 and S103, the dropping speed of 1 drop / second is not strictly limited, and the dropping speed may also be limited to 0.03-0.05 ml / s.

[0045] In some embodiments of the present invention, in step S2, the separation and purification treatment is preferably an extraction separation and purification method, such as adding an appropriate amount of 7.5wt% sodium bicarbonate solution and water and stirring, adding ethyl acetate for several extractions, combining the organic phases after extraction, concentrating and then evaporating to obtain the separated and purified chrysin derivative. However, it can be understood that the present application has no strict restrictions on the separation and purification method and the solvent used, and those skilled in the art can choose according to actual conditions.

[0046] In some embodiments of the present invention, the method for preparing a chrysin derivative comprises the steps of:

[0047] 1) Put chrysin into a round-bottom flask and add solvent I to obtain a mixed solution I;

[0048] 2) mixing the acyl chloride compound with the solvent II, and adding the mixture to the mixed solution I at a rate of 1 drop / second using a constant pressure dropping funnel to obtain a mixed solution II;

[0049] 3) diluting the acid-binding agent with solvent III, and adding the solution to the mixed solution II at a rate of 1 drop / second using a constant pressure dropping funnel. After the addition is completed, reacting at 0° C. to 120° C. for 0.5 to 3 hours, and adding distilled water to terminate the reaction to obtain a reaction product containing the chrysin derivative;

[0050] 4) adding 7.5% sodium bicarbonate solution and water, extracting the reaction product several times with ethyl acetate, combining the organic layers, concentrating, and evaporating to dryness to obtain the separated and purified chrysin derivative.

[0051] The reaction formula of the preparation method of the chrysin derivative of the present invention is at least one of the following two:

[0052]

[0053] In the reaction formula, the optional groups of R1 and R3 are the same as those in the above formula (I) and formula (II), and will not be repeated here.

[0054] The third aspect of the present invention provides a use of the chrysin derivative as described in the first aspect or the chrysin derivative prepared by the preparation method of the second aspect in the preparation of a drug for anti-inflammatory or anti-tumor treatment.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] (1) The cyclic hydrocarbon chrysin derivatives provided by the present invention introduce cyclic groups of cycloalkyl groups, heterocycloalkyl groups, aromatic groups or heteroaromatic groups into the chrysin skeleton to synthesize novel chrysin derivatives with anti-inflammatory and anti-tumor effects;

[0057] (2) The preparation method of the cyclic hydrocarbon chrysin derivative provided by the present invention can be prepared in one step, the reaction conditions are mild, the reaction raw materials are low in cost and easily available, and the required reaction reagents are green and environmentally friendly;

[0058] (3) The method for preparing the cyclic hydrocarbon chrysin derivatives provided by the present invention has a high yield of the cyclic hydrocarbon chrysin derivatives (e.g., 65% to 98%, and up to 98%). DETAILED DESCRIPTION

[0059] The "cycloalkyl" mentioned in the present invention refers to a cycloalkyl group containing at least 3 carbon atoms, such as a C3-C20 cycloalkyl group.

[0060] The "heterocycloalkyl" of the present invention refers to a non-aromatic heterocycle, which includes a saturated heterocycle or an unsaturated heterocycle (containing an unsaturated bond). One or more atoms forming the ring are heteroatoms, such as O, N, S or P atoms. The heterocycle is generally a monocyclic ring (having one ring), such as piperidinyl.

[0061] The term "aromatic group" in the present invention includes an organic residue derived from an aromatic hydrocarbon having 5 to 10 ring carbon atoms by removing one hydrogen, and may be a monocyclic aromatic group, a bicyclic aromatic group, or a polycyclic aromatic group. A monocyclic aromatic group is, for example, phenyl; a bicyclic aromatic group is, for example, naphthyl.

[0062] The term "heteroaromatic group" in the present invention includes aromatic heterocyclic groups containing one or more heteroatoms selected from O, N, S or P, wherein each heterocyclic group has 5 to 10 atoms in the ring system. Examples of suitable 5-10 membered heteroaryl groups include pyridyl, pyrimidyl, thienyl, pyrazolyl or furanyl.

[0063] The "alkoxy" mentioned in the present invention refers to an alkyl ether group (O-alkyl), such as C1~C20 alkoxy. Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0064] The "mono-substituted or di-substituted amino group" mentioned in the present invention refers to a group in which one or two hydrogen atoms in the amino group are replaced by a C1-C6 straight-chain alkyl group or a C3-C6 branched-chain alkyl group.

[0065] In order to make the present invention easier to understand, the present invention will be described in detail below in conjunction with examples, which are merely illustrative and are not intended to limit the scope of application of the present invention. The following examples are provided to further illustrate the method of the present invention. However, the present invention is not limited to the scope of the following examples.

[0066] In the following examples, all chemical reagents used are commercially available products, and unless otherwise specified, no special purification treatment is performed. In the following examples, the yield of chrysin derivatives is calculated as follows: yield = actual yield / theoretical yield * 100%.

[0067] The reaction formulas of the preparation methods of the chrysin derivatives of Examples 1-1 to 1-10 are as follows:

[0068]

[0069] The reaction was carried out according to the above reaction formula, and triethylamine was selected as the acid-binding agent; 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and then anhydrous acetone was added to dissolve it; cyclopentylcarbonyl chloride (6 mmol) shown in the reaction formula was mixed with solvent I in Table 1 below, and added dropwise to the round-bottom flask at a rate of 1 drop / second using a constant pressure dropping funnel; the acid-binding agent (30 mmol) was diluted with acetone, and added dropwise to the round-bottom flask at a rate of 1 drop / second using a constant pressure dropping funnel; the reaction was carried out at room temperature for 3 hours to obtain the chrysin derivative shown in I in the chemical formula.

[0070] The difference between Examples 1-1 to 1-10 is that different solvents I are used, as shown in Table 1 below:

[0071]

[0072]

[0073] As shown in Table 1 above, when N-methylpyrrolidone is used as solvent I, the yield is low; when acetonitrile, xylene, toluene, dimethyl sulfoxide or acetone are used as solvent I, the yield is high, all greater than 65%; when acetone is used as solvent I, the yield of the product is the highest, reaching 75%.

[0074] The reaction formulas of the preparation methods of the chrysin derivatives of Examples 2-1 to 2-4 are as follows:

[0075]

[0076] The reaction is carried out according to the above reaction formula; 1.50 g of chrysin (6 mmol) is placed in a round-bottom flask, and anhydrous acetone is added to dissolve it; the cyclopentylcarbonyl chloride (6 mmol) shown in the reaction formula is mixed with acetone, and is added dropwise to the round-bottom flask at a rate of 1 drop / second using a constant pressure dropping funnel; the acid binding agent (30 mmol) is diluted with acetone, and is added dropwise to the round-bottom flask at a rate of 1 drop / second using a constant pressure dropping funnel; the reaction is carried out at room temperature for 3 hours to obtain the chrysin derivative shown in the chemical formula II.

[0077] The difference between Examples 2-1 to 2-4 is that different acid binding agents are used, as shown in Table 2 below:

[0078]

[0079] It can be seen from Table 2 above that when triethylamine is used as the acid binding agent, the yield of the product is the highest, reaching 83%; when other substances are used as solvent I, the yields are all greater than 78%.

[0080] The reaction formulas of the preparation methods of the chrysin derivatives of Examples 3-1 to 3-5 are as follows:

[0081]

[0082] The reaction is carried out according to the above reaction formula; 1.50 g of chrysin (6 mmol) is placed in a round-bottom flask, and anhydrous acetone is added to dissolve it; the cyclopentylcarbonyl chloride (6 mmol) shown in the reaction formula is mixed with acetone, and is added dropwise to the round-bottom flask at a rate of 1 drop / second using a constant pressure dropping funnel; triethylamine (30 mmol) is diluted with acetone, and is added dropwise to the round-bottom flask at a rate of 1 drop / second using a constant pressure dropping funnel; the reaction is carried out at room temperature to obtain the chrysin derivative shown in the chemical formula III.

[0083] The difference between Examples 3-1 to 3-5 is that the reaction time at room temperature is different, as shown in Table 3 below:

[0084]

[0085] It can be seen from Table 3 above that when the reaction time is 1.5h to 2h, the yield of the product is the highest, reaching 83%; when the reaction time is greater than 0.5h, the yield is greater than 65%.

[0086] Example 4

[0087] The reaction formula of the preparation method of Example 4 is as follows:

[0088]

[0089] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0090] 2) 0.63 g of cyclopropylcarbonyl chloride (6 mmol) was dissolved in 30 ml of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0091] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 ml of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0092] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water. The organic layers were combined, concentrated and evaporated to dryness to obtain 1.53 g of chrysin derivative IV with a yield of 80.5%.

[0093] use 1 H NMR and 13 C NMR characterization results are as follows: 1H NMR(400MHz,Chloroform-d)δ12.65(s,1H),7.86-7.78(m,2H),7.40-7.50(m,3H),6.80(d,1H,J=2.0Hz),6.6 6(s,1H),6.51(d,1H,J=2.0Hz),1.80(tt,1H,J=8.1,4.6Hz),1.26-1.11(m,2H),1.02(dt,2H,J=8.3,3.5Hz); 13 C NMR(101MHz,Chloroform-d)δ182.89,172.55,164.67,161.87,156.75,156.18, 132.16,130.99,129.18,126.40,108.83,106.10,105.47,101.08,13.10,9.72.

[0094] Example 5

[0095] The reaction formula of the preparation method of Example 5 is as follows:

[0096]

[0097] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0098] 2) 0.71 g of cyclobutylcarbonyl chloride (6 mmol) was dissolved in 30 ml of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0099] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 ml of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0100] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water, and the organic layers were combined, concentrated and evaporated to dryness to obtain 1.71 g of chrysin derivative V with a yield of 85%.

[0101] use 1 H NMR and 13 C NMR characterization results are as follows: 1H NMR (400MHz, Chloroform-d) δ12.65 (s, 1H), 7.82 (dt, 2H, J = 6.6, 1.6Hz), 7.40-7.50 (m, 3H, J = 8.8, 7.8, 3.6Hz), 6. 79(d,1H,J=2.0Hz),6.67(s,1H),6.50(d,1H,J=2.0Hz),3.44-3.28(m,1H),2.49-2.22(m,4H),2.10-1.86(m,2H);

[0102] 13 C NMR(101MHz,Chloroform-d)δ182.89,172.96,164.66,161.88,156.77,156.29,132 .16,130.98,129.18,126.40,108.83,106.10,105.45,101.02,38.12,25.29,18.43.

[0103] Example 6

[0104] The reaction formula of the preparation method of Example 6 is as follows:

[0105]

[0106] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0107] 2) 0.80 g of cyclopentylcarbonyl chloride (6 mmol) was dissolved in 30 ml of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0108] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 ml of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0109] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water, and the organic layers were combined, concentrated and evaporated to dryness to obtain 1.74 g of chrysin derivative VI with a yield of 83%.

[0110] use 1 H NMR and 13 C NMR characterization results are as follows: 1H NMR(400MHz,Chloroform-d)δ12.64(s,1H),7.86-7.75(m,2H),7.55-7.41(m,3H),6.77(d,1H,J=2.0Hz) ,6.66(s,1H),6.48(d,1H,J=2.0Hz),2.52(tt,1H,J=11.2,3.7Hz),2.08-1.83(m,4H),1.80-1.53(m,4H);

[0111] 13 C NMR(101MHz,Chloroform-d)δ182.89,174.31,164.65,161.88,156.77,156.38,132 .16,130.98,129.18,126.40,108.80,106.09,105.47,101.04,43.90,30.06,25.90.

[0112] Example 7

[0113] The reaction formula of the preparation method of Example 7 is as follows:

[0114]

[0115] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0116] 2) 0.88 g of cyclohexylcarbonyl chloride (6 mmol) was dissolved in 30 ml of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0117] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 ml of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0118] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water. The organic layers were combined, concentrated and evaporated to dryness to obtain 1.90 g of chrysin derivative VII with a yield of 87%.

[0119] use 1 H NMR and 13 C NMR characterization results are as follows: 1H NMR(400MHz,Chloroform-d)δ12.64(s,1H),7.86-7.75(m,2H),7.55-7.41(m,3H),6.77(d,1H,J=2.0Hz),6.66(s, 1H),6.48(d,1H,J=2.0Hz),2.52(tt,1H,J=11.2,3.7Hz),1.81-1.72(m,2H),1.68-1.46(m,4H),1.43-1.15(m,4H);

[0120] 13 C NMR(101MHz,Chloroform-d)δ182.90,173.59,164.66,161.88,156.78,156.39,132.16 ,131.00,129.18,126.41,108.82,106.11,105.49,101.07,43.23,28.87,25.66,25.30.

[0121] Example 8

[0122] The reaction formula of the preparation method of Example 8 is as follows:

[0123]

[0124] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0125] 2) 1.88 g of cyclopropylcarbonyl chloride (18 mmol) was dissolved in 30 ml of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0126] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 ml of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0127] 4) The reaction product was extracted several times with ethyl acetate, 7.5% sodium bicarbonate solution and water, and the organic layers were combined, concentrated and evaporated to dryness to obtain 2.30 g of chrysin derivative VIII with a yield of 98%.

[0128] use 1 H NMR and 13 C NMR characterization results are as follows: 1H NMR(400MHz,Chloroform-d)δ7.82-7.75(m,2H),7.52-7.39(m,3H'),7.29(d,1H,J=2.2Hz),6.80(d,1H,J=2.3H z),6.61(s,1H),1.92(tt,1H,J=8.0,4.6Hz),1.80(tt,1H,J=7.9,4.6Hz),1.23-1.07(m,4H),1.11-0.89(m,4H);

[0129] 13 C NMR(101MHz,Chloroform-d)δ176.55,173.09,172.28,162.48,157.67,154.09,150.32,13 1.76,131.13,129.10,126.22,115.16,113.83,109.03,108.57,13.29,13.07,9.83,9.29.

[0130] Example 9

[0131] The reaction formula of the preparation method of Example 9 is as follows:

[0132]

[0133] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0134] 2) 0.78 g of furanylcarbonyl chloride (6 mmol) was dissolved in 30 mL of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0135] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 mL of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0136] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water. The organic layers were combined, concentrated and evaporated to dryness to obtain 1.73 g of chrysin derivative IX with a yield of 83%.

[0137] Example 10

[0138]

[0139] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0140] 2) 0.93 g of methylbenzoyl chloride (6 mmol) was dissolved in 30 mL of anhydrous acetone and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0141] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 mL of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0142] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water. The organic layers were combined, concentrated and evaporated to dryness to obtain 1.90 g of chrysin derivative X with a yield of 85%.

[0143] Embodiment 11

[0144]

[0145] 1) 1.50 g of chrysin (6 mmol) was placed in a round-bottom flask, and 500 mL of anhydrous acetone was added to dissolve the mixture to obtain a mixed solution I;

[0146] 2) 0.85 g of pyridylcarbonyl chloride (6 mmol) was dissolved in 30 mL of anhydrous acetone, and added dropwise to the mixed solution I at a rate of 0.05 ml / s using a constant pressure dropping funnel to obtain a mixed solution II;

[0147] 3) After the addition of the acyl chloride compound, 3.00 g of triethylamine (30 mmol) was dissolved in 30 mL of anhydrous acetone and added dropwise at a rate of 0.05 ml / s using a constant pressure dropping funnel; after the addition was completed, the reaction progress was monitored by thin layer chromatography, and after reacting at room temperature (25°C) for 1.5 h, distilled water was added to terminate the reaction to obtain a reaction product;

[0148] 4) The reaction product was extracted multiple times with ethyl acetate, 7.5% sodium bicarbonate solution and water. The organic layers were combined, concentrated and evaporated to dryness to obtain 1.75 g of chrysin derivative XI with a yield of 81%.

[0149] The yield and purity of the products obtained in Examples 4-11 are shown in Table 4 below:

[0150]

[0151] It can be seen from the above Examples 4-11 that the method for preparing chrysin derivatives of the present invention has a maximum yield of 98%.

[0152] It should be noted that the embodiments described above are only used to explain the present invention and do not constitute any limitation to the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the words used therein are descriptive and explanatory words, rather than restrictive words. The present invention may be modified as specified within the scope of the claims of the present invention, and the present invention may be revised without departing from the scope and spirit of the present invention. Although the present invention described therein relates to specific methods, materials and embodiments, it does not mean that the present invention is limited to the specific examples disclosed therein, on the contrary, the present invention can be extended to all other methods and applications with the same functions.

Claims

1. A chrysin derivative having a structure shown in formula (I): In formula (I): R1 is selected from substituted or unsubstituted cycloalkyl I, substituted or unsubstituted heterocycloalkyl I, substituted or unsubstituted aryl I and substituted or unsubstituted heteroaryl I; R2 is selected from hydroxyl or a group represented by formula (II), wherein R3 is selected from substituted or unsubstituted cycloalkyl II, substituted or unsubstituted heterocycloalkyl II, substituted or unsubstituted aromatic II and substituted or unsubstituted heteroaromatic II; the dotted bond indicates the connection position; Preferably, in R1 and R3, the substituents on the substituted cycloalkyl I, substituted cycloalkyl II, substituted heterocycloalkyl I, substituted heterocycloalkyl II, substituted aromatic I, substituted aromatic II, substituted heteroaromatic I and substituted heteroaromatic II are selected from C1-C20 straight-chain alkyl, C3-C20 branched-chain alkyl, C1-C20 alkoxy and mono-substituted or di-substituted amino; Preferably, the heterocycloalkyl group I has 5-10 ring-forming atoms I, wherein at least one skeleton ring-forming atom I is O, N, S or P; Preferably, the heterocycloalkyl group II has 5-10 skeleton ring atoms II, wherein at least one skeleton ring atom II is O, N, S or P; Preferably, the heteroaromatic group I has 5 to 10 skeleton ring atoms III, wherein at least one skeleton ring atom III is O, N, S or P; Preferably, the heteroaromatic group II has 5 to 10 skeleton ring atoms IV, wherein at least one skeleton ring atom IV is O, N, S or P.

2. The chrysin derivative according to claim 1, characterized in that The cycloalkyl group I and cycloalkyl group II are independently selected from one of the C3 to C20 cycloalkyl groups; And / or, the heterocycloalkyl group I and the heterocycloalkyl group II are independently selected from one of furanyl, tetrahydrofuranyl, piperidinyl, pyridinyl and bipyridinyl; and / or, the heteroaromatic group I and the heteroaromatic group II are independently selected from one of pyridyl, pyrimidinyl, thienyl, pyrazolyl and furanyl; And / or, the aromatic group I and the aromatic group II are independently selected from a monocyclic aromatic group or a condensed-ring aromatic group, preferably a benzyl group or a naphthyl group.

3. The method for preparing the chrysin derivative according to claim 1 or 2, comprising the steps of: S1, reacting a mixed solution containing solvent I, chrysin and an acyl chloride compound to obtain a reaction product containing a chrysin derivative represented by formula (I); and Optionally, S2, separating and purifying the reaction product to obtain the separated and purified chrysin derivative, in, The acyl chloride compound is selected from one or two of the compounds represented by formula (III), When the acyl chloride compound is one, R1 in Formula I is R, and R2 is OH; When there are two types of acyl chloride compounds, they are In formula I, R1 is R' and R2 is R".

4. The preparation method according to claim 3, characterized in that: In step S1, the molar ratio of chrysin to the acyl chloride compound in the mixed solution is 1:10-1; preferably 1:1-3; And / or, in step S1, the solvent I is selected from at least one of acetone, tetrahydrofuran, dioxane and chloroform.

5. The preparation method according to claim 3 or 4, characterized in that: The mixed solution in step S1 further comprises an acid-binding agent, and the molar ratio of the chrysin to the acid-binding agent is 1:10-1; preferably 1:4-6; Preferably, the acid binding agent is selected from at least one of organic bases; more preferably selected from at least one of triethylamine, pyridine, picoline, N,N-dimethylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, dioxydimethyl ether acetate and N-methylpyrrolidone.

6. The preparation method according to any one of claims 3 to 5, characterized in that: The reaction conditions of step S1 include: temperature of 0°C to 120°C; and / or time of 0.5 to 3 hours, preferably 1.5 to 2 hours.

7. The preparation method according to any one of claims 3 to 6, characterized in that: The step S1 comprises: S101, obtaining a mixed solution I containing the chrysin and the solvent I; S102, mixing the first solution containing the acyl chloride compound and the solvent II with the mixed solution I to obtain a mixed solution II containing the chrysin derivative; S103, mixing the second solution containing the acid binding agent and the solvent III with the mixed solution II to obtain a reaction product containing the chrysin derivative.

8. The preparation method according to claim 7, characterized in that: In step S102, the solvent II is at least one of acetone, tetrahydrofuran, dioxane and chloroform; and / or, in step S102, the first solution is added dropwise to the mixed solution I to obtain the mixed solution II; And / or, in step S103, the solvent III is at least one of acetone, tetrahydrofuran, dioxane and chloroform; And / or, in step S103, the second solution is added dropwise to the mixed solution II to obtain the mixed solution III.

9. Use of the chrysin derivative according to claim 1 or 2 in the preparation of anti-inflammatory or anti-tumor drugs.

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