CN112321554A - Genistein structure modified derivative and synthesis method thereof - Google Patents
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- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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Abstract
The invention discloses a genistein structure modified derivative and a synthesis method thereof, wherein the genistein structure modified derivative has a structure shown in a formula (I):
in the formula (I), Ar1、Ar2Is selected from
Wherein, is connected with C or S, R is H, cyano, nitro, hydroxyl, phenyl, methylenedioxy, C1‑C6Alkyl radical, C2‑C6Alkenyl radical, C1‑C6Alkoxy, halogen, halogeno C1‑C6Alkyl or halo C1‑C6An alkoxy group. The genistein structure-modified derivative and the synthesis method provided by the invention have the advantages of high product yield, high purity, high atom economy and the like, and have good scientific researchThe compound has the advantages of high value and application prospect, provides a brand new route for the preparation of the compound, can play an important role in the fields of drug intermediates, pesticide intermediates and the like, reduces the production cost, and has good application value and potential in industry and scientific research.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, relates to a genistein structure modified derivative and a synthesis method thereof, and particularly relates to a synthesis method of a 2-aryl-N-sulfonyl acetimidoic acid genistein-7-ester derivative.
Background
Genistein, also called genistein, is a natural compound extracted from leguminous plants, has multiple biological activities of oxidation resistance, cancer resistance, inflammation resistance, ulcer resistance, cardiovascular protection, estrogen-like and the like, and has gradually become a hotspot of researches of researchers at home and abroad in recent years. Researches show that genistein and its glucoside have weak estrogen-like activity, have certain effects of resisting cancer, preventing osteoporosis of middle-aged and elderly people, improving female climacteric syndrome, treating cardiovascular diseases, etc., also have certain effects of preventing alopecia and resisting oxidation, and can be widely used as nutritional food supplement.
However, the biological activity of genistein is low, and the structural modification of genistein by taking genistein as a lead compound is an effective way for improving the activity of genistein. The total synthesis modification technology of the genistein glucoside is biased to the synthesis of the carbon glucoside at present, and the semi-synthesis modification is mainly focused on the synthesis of the oxygen glucoside. Although there are various methods for synthesizing genistein glycoside, there is no method which is very effective and has wide adaptability from the viewpoint of yield and stereoselectivity. In order to better expand the utilization rate of genistein, it is necessary to develop a method for modifying the structure of genistein, which has the advantages of easily available raw materials, simple conditions and high efficiency.
Based on the above, the invention designs a 2-aryl-N-sulfonyl acetimidoic acid genistein-7-ester derivative and a synthetic method thereof, so as to solve the above-mentioned problems.
Disclosure of Invention
The invention mainly aims to provide a genistein structure modified derivative and a synthesis method thereof, so as to overcome the defects in the prior art.
In order to achieve the above object, the technical solution adopted by the embodiment of the present invention includes:
the embodiment of the invention provides a genistein structure modified derivative, which has a structure shown in a formula (I):
in the formula (I), Ar1、Ar2Is selected from
Wherein, is connected with C or S, R is H, cyano, nitro, hydroxyl, phenyl, methylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl or halo C1-C6An alkoxy group.
Wherein, C1-C6Alkyl means a straight or branched chain alkyl group having 1 to 6 carbon atoms, which includes C1Alkyl radical, C2Alkyl radical, C3Alkyl radical, C4Alkyl radical, C5Alkyl or C6Alkyl, which may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl, and the like.
Wherein, C1-C6Alkoxy means C1-C6A group in which an alkyl group is bonded to an O atom.
Wherein, the meaning of the halogen refers to halogen elements and can be F, Cl, Br or I.
Wherein is halo C1-C6Alkyl means C substituted by halogen1-C6Alkyl groups, which may be trifluoromethyl, pentafluoroethyl, difluoromethyl, chloromethyl, and the like.
Wherein is halo C1-C6The meaning of alkoxy means C substituted by halogen1-C6The alkoxy group may be trifluoromethoxy, pentafluoroethoxy, difluoromethoxy, chloromethoxy, etc.
The embodiment of the invention also provides a synthesis method of the genistein structure modified derivative, which comprises the following steps:
taking a copper compound as a catalyst, and carrying out cycloaddition, ring-opening rearrangement and nucleophilic addition reaction on genistein in a formula (II), terminal alkyne in a formula (III) and sulfonyl azide in a formula (IV) in an organic solvent to obtain a genistein structure modified derivative in the formula (I), namely a 2-aryl-N-sulfonyl acetyl imido genistein-7-ester derivative;
further, the synthesis method of the genistein structure modified derivative comprises the following steps: taking a copper compound as a catalyst, and in the presence of a ligand, in an organic solvent, carrying out cycloaddition, ring-opening rearrangement and nucleophilic addition reactions on genistein in a formula (II), terminal alkyne in a formula (III) and sulfonyl azide in a formula (IV) to obtain a genistein structure modified derivative in the formula (I), namely a 2-aryl-N-sulfonyl acetimidoyl genistin-7-ester derivative;
further, the copper compound includes any one of copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, copper thiophene-2-carboxylate, or cuprous acetate, preferably cuprous iodide or cuprous chloride, and most preferably cuprous iodide.
Further, the organic solvent comprises one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, chlorobenzene, benzene, xylene, dimethyl sulfoxide or N-methylpyrrolidone, preferably acetonitrile or dimethyl sulfoxide, and most preferably dimethyl sulfoxide.
Further, the molar ratio of the genistein in the formula (II), the terminal alkyne in the formula (III) and the sulfonyl azide in the formula (IV) is 1:1-3: 1-3.
Further, the reaction temperature of the cycloaddition, the ring-opening rearrangement and the nucleophilic addition reaction is 25-120 ℃, and the reaction time is 1-24 hours.
Further, the molar ratio of genistein to copper compound in the formula (II) is 1: 0.05-0.40.
Further, the molar ratio of genistein to ligand in the formula (II) is 1: 0.10-2.
Wherein the ratio of genistein in formula (II) to solvent in ml is 1:5-15 in millimole, i.e. 5-15 ml of solvent is used for every 1 millimole of genistein in formula (II), and can be 1:5, 1:8, 1:10, 1:12 or 1: 15.
Further, the ligand includes any one of acetonitrile, N-dimethylformamide, triethylamine, N-tributylamine, tri-tert-butylamine, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine or 1, 10-phenanthroline, preferably tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine or acetonitrile, most preferably tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine.
Further, the method also comprises post-treatment after the synthesis reaction is finished, and specifically comprises the following steps: cooling the reaction system to room temperature, adding water and ethyl acetate, extracting for 1-3 times, wherein the volume ratio of water to ethyl acetate is 2-5:1, collecting the upper layer liquid, and extracting with anhydrous Na2SO4Drying, evaporating to remove ethyl acetate by using a rotary evaporator after drying, passing the residue through a 200-mesh 300-mesh silica gel column, and taking ethyl acetate/petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-15, thereby obtaining the target product, namely the compound shown in the formula (I).
The post-treatment can also be any one or combination of extraction, concentration, crystallization, recrystallization and column chromatography purification.
As another exemplary post-treatment means, for example, there may be mentioned: after the reaction is completed, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline solution in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 200-mesh-300-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-10, so as to obtain the 2-aryl-N-sulfonyl acetimido genistein-7-ester derivative target product in the formula (I).
Preferably, genistein in (II), the terminal alkyne in formula (III) and the sulfonyl azide in formula (IV) are directly available.
Compared with the prior art, the invention has the following beneficial effects:
the invention uses copper compound as catalyst, amine compound as ligand, 2-aryl-N-sulfonyl acetyl imido acid genistein-7-ester derivative in formula (I) can be obtained by one step through reaction of genistein in formula (II), terminal alkyne in formula (III) and sulfonyl azide in formula (IV), has the advantages of single product selectivity, high yield, high purity, high atom economy and the like, has good scientific research value and application prospect, provides a brand new route and a new thought for structure modification of genistein, can play an important role in the fields of drug intermediates, pesticide intermediates and the like, finds new drugs, and has good application value and potential in industry and scientific research.
Detailed Description
The present inventors have conducted intensive studies in order to find a novel synthetic method for structural modification of genistein, after having paid a lot of creative efforts, thereby completing the present invention. The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Adding the compounds of the formulas (II), (III) and (IV), cuprous iodide (CuI) and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) into dimethyl sulfoxide (DMSO), and then stirring and sealing the mixture at room temperature for reaction for 24 hours; wherein the molar ratio of the compound of formula (II) to copper iodide (CuI) is 1:0.05, the molar ratio of the compound of formula (II) to tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.1, the molar ratio of the compound of formula (II) to the compounds of formula (III) and (IV) is 1:1:1, and the ratio of the compound of formula (II) to dimethylsulfoxide, DMSO, in milliliters (ml), is 1:5 in millimoles (mmol).
After the reaction is finished, naturally cooling the reaction system to room temperature, adding a mixed solution of ethyl acetate and saturated saline in an equal volume ratio, performing oscillation extraction for 2-4 times, collecting an organic layer, drying, performing rotary evaporation and concentration to obtain a crude product, performing 300-400-mesh silica gel column chromatography on the crude product, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5, so as to obtain a target product of the compound (C) of the formula (I) which is a white solid30H23NO7S) yield 82.4% and purity 98.6% (HPLC).
Melting point: 161.2-163.7 ℃.
Nuclear magnetic resonance: 1HNMR (400MHz, dimethyl sulfoxide DMSO-d6) delta 12.98(s, 1H), 9.65(s, 1H), 8.50(s, 1H), 7.83-7.27(m, 11H), 6.87-6.84(m, 3H), 6.50(s, 1H), 2.44(s, 3H), 2.37(s, 2H).
13CNMR (400MHz, dimethyl sulfoxide DMSO-d6) delta 181.3, 162.0(2C), 158.2, 156.7, 155.8, 153.9, 146.8, 142.3, 141.9, 131.4, 130.9(2C), 130.7(2C), 129.8(2C), 128.8(2C), 126.1(2C), 123.7, 121.0, 115.6(2C), 110.1, 105.2, 101.8, 21.7, 21.4.
Example 2
Adding the compounds of the above formulas (II), (III) and (IV), cuprous iodide (CuI), and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) to dimethyl sulfoxide (DMSO), heating to 40 ℃, and carrying out a sealing reaction for 12 hours with stirring at the temperature; wherein the molar ratio of the compound of formula (II) to copper iodide (CuI) is 1:0.2, the molar ratio of the compound of formula (II) to tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.2, the molar ratio of the compound of formula (II) to the compounds of formula (III) and (IV) is 1:2:2, and the ratio of the compound of formula (II) to dimethylsulfoxide, DMSO, in milliliters (ml), is 1:8 in millimoles (mmol).
After the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:8, so as to obtain a target product (C) of the compound (I) which is a white solid30H22ClNO7S) yield 81.6% and purity 97.5% (HPLC).
Melting point: 155.4-157.2 ℃.
Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 12.97(s, 1H), 9.66(s, 1H), 8.47(s, 1H), 7.83(d, J ═ 8.4Hz, 2H), 7.72-7.70(m, 1H), 7.49(d, J ═ 8.0Hz, 2H), 7.38-7.34(m, 4H), 7.28(s, 1H), 6.85-6.82(m, 3H), 6.48(d, J ═ 2.2Hz, 1H), 2.42(s, 3H), 2.36(s, 2H).
13CNMR (400MHz, dimethyl sulfoxide DMSO-d6) delta 180.9, 161.6(2C), 157.7, 156.3, 155.3, 153.5, 146.4, 141.9, 141.5, 131.0, 130.4(2C), 130.2(2C), 129.3(2C), 128.4(2C), 125.6(2C), 123.2, 120.5, 115.2(2C), 109.6, 104.8, 101.3, 21.2, 21.0.
Example 3
Adding the compounds of the above formulas (II), (III) and (IV), cuprous iodide (CuI), and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) to dimethyl sulfoxide (DMSO), heating to 30 ℃, and carrying out a sealing reaction for 8 hours with stirring at the temperature; wherein the molar ratio of the compound of formula (II) to copper iodide (CuI) is 1:0.15, the molar ratio of the compound of formula (II) to tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:0.3, the molar ratio of the compound of formula (II) to the compounds of formula (III) and (IV) is 1:1.5:1.5, and the ratio of the compound of formula (II) to dimethyl sulfoxide DMSO in milliliters (ml) is 1:6 in millimoles (mmol).
After the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:6, so as to obtain a target product (C) of the compound (I) which is a white solid31H25NO7S) yield 80.7% and purity 97.8% (HPLC).
Melting point: 158.2-160.3 ℃.
Nuclear magnetic resonance: 1HNMR (400MHz, dimethyl sulfoxide DMSO-d6) delta 12.98(s, 1H), 9.66(s, 1H), 8.50(s, 1H), 7.85-7.27(m, 10H), 6.87-6.84(m, 3H), 6.50(s, 1H), 2.43(s, 3H), 2.37(s, 3H), 2.29(s, 2H).
13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 181.3, 162.0, 158.2, 156.7, 155.8(2C), 153.9, 146.8, 142.3, 141.9, 131.4, 130.9(2C), 130.7(2C), 129.8(2C), 128.8(2C), 126.1(2C), 123.7, 120.8, 115.6(2C), 110.1, 105.2, 101.8, 21.7(2C), 21.4.
Example 4
Adding the compounds of the above formulae (II), (III) and (IV), copper iodide (CuI), and tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) to dimethyl sulfoxide (DMSO), then heating to 60 ℃, and reacting for 12 hours with stirring in air at that temperature; wherein the molar ratio of the compound of formula (II) to copper iodide (CuI) is 1:0.4, the molar ratio of the compound of formula (II) to tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) is 1:2, the molar ratio of the compound of formula (II) to the compounds of formula (III) and (IV) is 1:3:3, and the ratio of the compound of formula (II) to dimethyl sulfoxide DMSO in milliliters (ml) is 1:15 in millimoles (mmol).
After the reaction is completed, naturally cooling the reaction system to room temperature, distilling under reduced pressure to remove the solvent to obtain a crude product, carrying out chromatography on the crude product by a 200-mesh 300-mesh silica gel column, and taking a mixed solution of ethyl acetate and petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:15, so as to obtain a target product (C) of the compound (I) which is a white solid29H19NO8S) yield 81.8% and purity 98.7% (HPLC).
Melting point: 161.0-165.2 ℃.
Nuclear magnetic resonance: 1HNMR (400MHz, dimethylsulfoxide DMSO-d6) δ 13.02(s, 1H), 9.71(s, 1H), 8.53(s, 1H), 8.02-7.99(m, 2H), 7.92-7.87(m, 2H), 7.77-7.73(m, 2H), 7.65-7.60(m, 2H), 7.43-7.41(m, 4H), 6.90-6.87(m, 3H), 6.53(d, J ═ 2.2Hz, 1H).
13CNMR (400MHz, dimethylsulfoxide DMSO-d6) delta 181.3, 162.0(2C), 158.2, 156.7, 155.8, 153.9, 144.6, 135.9(2C), 134.3, 132.3(2C), 130.7(2C), 130.5(2C), 129.4(2C), 128.8(2C), 126.0(2C), 123.7, 121.0, 115.6, 110.2, 105.3, 101.8.
Comparative examples 5 to 12: investigation of the catalyst
Examples 5 to 12 were each carried out in the same manner as in examples 1 to 4 except that the CuI therein was replaced with the following copper compound, and the copper compounds used, the correspondence relationships between examples and the yields of the respective products are shown in the following tables.
The results obtained are shown in the following table.
It can be seen that when other copper compounds are used, the corresponding products are obtained, and the reaction of the monovalent copper compounds is generally more effective than that of the divalent, which demonstrates that the monovalent copper compound catalyst of the process of the present invention has good catalytic properties for the substrate, with CuI being the most effective catalyst for the reaction.
Comparative examples 13 to 20: investigation of ligands
Comparative examples 13 to 20 were each carried out in the same manner as in examples 1 to 4 except that the ligand was changed from tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) to the following ligand, and the ligands used, the correspondence relationship between examples and the yields of the respective products are shown in the following tables.
It can be seen that tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) has suitable coordination among all ligands, while the other ligands have significantly reduced yields or even no product is obtained. It can also be seen that tertiary amines such as triethylamine (Et3N) which are very similar to tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) also have a relatively good complexing effect, while other 1, 10-phenanthroline (Phen) having a strong complexing property and the like are significantly reduced.
Comparative examples 25 to 32: investigation of solvents
Examples 25 to 32 were each carried out in the same manner as in examples 1 to 4 except that the solvent was replaced with dimethyl sulfoxide DMSO as follows, and the solvents used, the correspondence among examples, and the yields of the respective products were as shown in the following tables.
It can be seen that the solvent also has some influence on the final result, with dimethyl sulfoxide DMSO having the best effect, DMF and other solvents all having a greatly reduced yield.
From the above, it is clear from all the examples that when the method of the present invention is used, the compounds of formulae (II), (III) and (IV) can be smoothly reacted to obtain the desired product, and the yield is good, the post-treatment is simple, and the effects are obtained depending on the combined synergistic effect of a plurality of factors such as catalyst, ligand and solvent, and when any one of them is changed, the yield is significantly reduced.
The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.
The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.
Throughout this disclosure (the present invention), where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition taught by the present invention also consists essentially of, or consists of, the recited components, and the process taught by the present invention also consists essentially of, or consists of, the recited process steps.
Unless specifically stated otherwise, use of the terms "comprising", "including", "having" or "having" is generally to be understood as open-ended and not limiting.
It should be understood that the order of steps or the order in which particular actions are performed is not critical, so long as the teachings of the invention remain operable. Further, two or more steps or actions may be performed simultaneously.
In addition, the inventors of the present invention have also made experiments with other materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.
While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.
Claims (10)
1. A genistein structurally modified derivative having the structure shown in formula (I):
in the formula (I), Ar1、Ar2Is selected from
Wherein, is connected with C or S, R is H, cyano, nitro, hydroxyl, phenyl, methylenedioxy, C1-C6Alkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy, halogen, halogeno C1-C6Alkyl or halo C1-C6An alkoxy group.
2. A method for synthesizing derivatives structurally modified by genistein, which is characterized by comprising the following steps:
taking a copper compound as a catalyst, and carrying out cycloaddition, ring-opening rearrangement and nucleophilic addition reaction on genistein in a formula (II), terminal alkyne in a formula (III) and sulfonyl azide in a formula (IV) in an organic solvent to obtain a genistein structure modified derivative in the formula (I), namely a 2-aryl-N-sulfonyl acetyl imido genistein-7-ester derivative;
3. the method for synthesizing structurally modified genistein derivatives according to claim 2, which comprises: taking a copper compound as a catalyst, and in the presence of a ligand, in an organic solvent, carrying out cycloaddition, ring-opening rearrangement and nucleophilic addition reactions on genistein in a formula (II), terminal alkyne in a formula (III) and sulfonyl azide in a formula (IV) to obtain a genistein structure modified derivative in the formula (I), namely a 2-aryl-N-sulfonyl acetimidoyl genistin-7-ester derivative;
4. the method for synthesizing structurally modified genistein derivatives according to claim 3, further comprising: after the synthesis reaction is finished, carrying out post-treatment;
and/or, the post-processing comprises: cooling the reaction system to room temperature, adding water and ethyl acetate, extracting for 1-3 times, wherein the volume ratio of water to ethyl acetate is 2-5:1, collecting the upper layer liquid, and using anhydrous Na2SO4Drying, evaporating to remove ethyl acetate by using a rotary evaporator after drying, passing the residue through a 200-mesh 300-mesh silica gel column, and taking ethyl acetate/petroleum ether as an eluent, wherein the volume ratio of the ethyl acetate to the petroleum ether is 1:5-15, thereby obtaining the target product, namely the compound shown in the formula (I).
5. The method for synthesizing structurally modified genistein derivatives according to claim 2, 3 or 4, wherein: the copper compound comprises any one of copper acetate, copper chloride, copper bromide, copper acetylacetonate, copper trifluoroacetate, copper trifluoromethanesulfonate, copper oxide, cuprous iodide, cuprous bromide, cuprous chloride, thiophene-2-copper formate or cuprous acetate.
6. The method for synthesizing structurally modified genistein derivatives according to claim 2, 3 or 4, wherein: the organic solvent comprises one or more of methanol, ethanol, acetonitrile, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, chlorobenzene, benzene, xylene, dimethyl sulfoxide or N-methylpyrrolidone.
7. The method for synthesizing structurally modified genistein derivatives according to claim 2, 3 or 4, wherein: the molar ratio of the genistein in the formula (II), the terminal alkyne in the formula (III) and the sulfonyl azide in the formula (IV) is 1:1-3: 1-3.
8. The method for synthesizing structurally modified genistein derivatives according to claim 2, 3 or 4, wherein: the reaction temperature of the cycloaddition, the ring-opening rearrangement and the nucleophilic addition reaction is 25-120 ℃, and the reaction time is 1-24 hours.
9. The method for synthesizing structurally modified genistein derivatives according to claim 3 or 4, wherein: the molar ratio of genistein to copper compound in formula (II) is 1:0.05-0.40, and/or the molar ratio of genistein to ligand in formula (II) is 1: 0.10-2.
10. The method for synthesizing structurally modified genistein derivatives according to claim 3 or 4, wherein: the ligand comprises any one of acetonitrile, N-dimethylformamide, triethylamine, N-tributylamine, tri-tert-butylamine, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, 2-iodopyridine, tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine or 1, 10-phenanthroline.
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| CN101544585A (en) * | 2009-05-07 | 2009-09-30 | 同济大学 | Method for preparing (Z)-4-(2-bromovinyl) benzenesulfonimide |
| CN105732560A (en) * | 2016-01-28 | 2016-07-06 | 中国药科大学 | Genistein derivative as well as preparation method and application thereof in pharmacy |
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| CN101544585A (en) * | 2009-05-07 | 2009-09-30 | 同济大学 | Method for preparing (Z)-4-(2-bromovinyl) benzenesulfonimide |
| CN105732560A (en) * | 2016-01-28 | 2016-07-06 | 中国药科大学 | Genistein derivative as well as preparation method and application thereof in pharmacy |
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