CN113651755B - 4-azafluorene compound and preparation method and application thereof - Google Patents
4-azafluorene compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a 4-azafluorene compound and a preparation method and application thereof. The structural general formula of the 4-azafluorene compound is shown as a formula I:
in the formula I, R 1 One selected from aryl or alkyl, R 2 One selected from aryl or alkyl, R 3 One kind selected from alkoxy, fluoroalkyl or hydrogen atom, R 4 Selected from alkyl groups. The 4-azafluorene compound is an important organic molecule parent nucleus structure and can be applied to the synthesis of complex natural products, bioactive molecules or functional material molecules; the application adopts the enynone compound and the isocyanoacetic ester compound to carry out the series cyclization reaction to prepare the 4-azafluorene compound, the reaction condition is mild, the operation is simple and efficient, the raw materials and the reagents are stable and easy to obtain, no metal reagent is needed, and the practicability is strong.
Description
Technical Field
The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a 4-azafluorene compound and a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
The 4-azafluorene compound has an indenopyridine structure as a core skeleton, is a mother nucleus structure of some alkaloids, exists in various natural active products, medicines and bioactive molecules, has activities of resisting cancer, allergy, inflammation, bacteria and the like, and exists in various medicines such as antimalarial drugs, vasodilators, anesthetics, anticonvulsants, antiepileptics and the like.
In addition, the azafluorene compound can be used as a good luminescent ligand, and has important significance in the fields of electronics, luminescent materials and the like. Bifluorene analogs containing pyridyl moieties such as Hwu and efficient electron transport materials as hosts are mixed with various red (Ir, Ru, Os and Pt) and green (Ir) phosphors containing heavy metals to obtain high efficiency phosphorescent OLEDs with simple device structures. Wong et al provide novel heteroarene intercalated and bipolar tri-fluorene analogs, the physical properties of the parent tri-fluorene are significantly altered upon incorporation of the heteroarene units as a component, and the presence of heteroarenes and their co-planarity with the adjacent phenylene rings provide these novel tri-fluorene analogs with properties useful in light emitting devices.
At present, although chemical workers have developed a lot of 4-azafluorene compounds and synthesis methods, the variety of 4-azafluorene compounds is still relatively small, and there are still limitations in selecting applications, and most of the existing synthesis methods are based on cyclization reaction of 2-aryl pyridine or aryl (pyridine-3-yl) ketone derivative substrates, and require pre-construction of five-membered rings in a tricyclic framework, metal reagents and carrying out under the condition of isolating water or oxygen, and the steps are complicated.
Therefore, it is important to develop a new 4-azafluorene compound and provide a relatively simple and efficient synthesis method.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a 4-azafluorene compound and a preparation method thereof, wherein the 4-azafluorene compound is an important organic molecule parent nucleus structure and can be applied to the synthesis of complex natural products, bioactive molecules or functional material molecules; the application adopts the enynone compound and the isocyanoacetic ester compound to carry out the series cyclization reaction to prepare the 4-azafluorene compound, the reaction condition is mild, the operation is simple and efficient, the raw materials and the reagents are stable and easy to obtain, no metal reagent is needed, and the practicability is strong.
In order to solve the technical problems, the invention provides the following technical scheme:
the invention provides a 4-azafluorene compound, which has a structural general formula shown in formula I:
in the formula I, R 1 One selected from aryl or alkyl, R 2 One selected from aryl or alkyl, R 3 One kind selected from alkoxy, fluoroalkyl or hydrogen atom, R 4 Selected from alkyl groups.
In a second aspect, the present invention provides a process for the preparation of a compound of formula i: the enynone compound and the isocyanoacetic ester compound are subjected to a series cyclization reaction to obtain the compound shown in the formula I.
The reaction scheme is as follows:
in a third aspect, the invention provides a pharmaceutical composition comprising a compound of formula I as described above, or an isomer or solvate or pharmaceutically acceptable molecule thereof.
The fourth aspect of the invention provides an application of a 4-azafluorene compound shown in formula I and a derivative thereof in preparation of a cervical cancer cell growth inhibitor.
One or more embodiments of the present invention have at least the following advantageous effects:
(1) the polysubstituted 4-azafluorene compound provided by the invention is an important organic molecule parent nucleus structure, can be applied to the synthesis of complex natural products, bioactive molecules or functional material molecules, and therefore has a very important position in the fields of organic synthesis and reaction diversity. In addition, the 4-azafluorene compound can also be used as an important organic synthon intermediate for synthesizing important 4-azafluorenone derivatives.
(2) The synthesis method of the 4-azafluorene compound provided by the invention does not need to construct five-membered rings in a tricyclic framework in advance, does not need to isolate water or oxygen, only needs to undergo first intramolecular cyclization and formation of a hexahydric azayne positive ion intermediate under mild conditions of alkali catalysis, further performs intramolecular cyclization reaction, and then performs proton migration, oxidative aromatization and the like to obtain a final product. The preparation method has the advantages of mild conditions, simple and efficient operation, stable and easily obtained raw materials and reagents, no need of metal reagents, strong practicability and suitability for synthesizing various multi-substituted 4-azafluorene compounds. Experimental data show that the 4-azafluorene compound derivative provided by the invention has certain Hela inhibitory activity and can be used as a cervical cancer cell growth inhibitor.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of a 4-azafluorene compound obtained in example 1 of the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 3 of the present invention;
FIG. 4 is a nuclear magnetic carbon spectrum of a 4-azafluorene compound obtained in example 3 of the present invention;
FIG. 5 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 6 of the present invention;
FIG. 6 is a nuclear magnetic carbon spectrum of a 4-azafluorene compound obtained in example 6 of the present invention;
FIG. 7 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 8 of the present invention;
FIG. 8 is a nuclear magnetic carbon spectrum of a 4-azafluorene compound obtained in example 8 of the present invention;
FIG. 9 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 10 of the present invention;
FIG. 10 is a nuclear magnetic carbon spectrum of a 4-azafluorene compound obtained in example 10 of the present invention;
FIG. 11 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 12 of the present invention;
FIG. 12 shows a nuclear magnetic carbon spectrum of a 4-azafluorene compound obtained in example 12 of the present invention.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As described in the background art, the types of 4-azafluorene compounds in the prior art are few, and there still exists a limitation in selecting and applying the compounds, and most of the existing synthetic methods are based on the cyclization reaction of 2-aryl pyridine or aryl (pyridine-3-yl) ketone derivative substrates, and need to construct five-membered rings in a tricyclic framework in advance, and also need metal reagents, and the steps are performed under the condition of isolating water or oxygen, so that the steps are complicated.
In order to solve the technical problems, the invention provides a 4-azafluorene compound in a first aspect, wherein the structural general formula of the compound is shown as formula I:
in the formula I, R 1 One selected from aryl or alkyl, R 2 One selected from aryl or alkyl, R 3 One selected from alkoxy, fluoroalkyl or hydrogen atom, R 4 Selected from alkyl groups.
The polysubstituted 4-azafluorene compound provided by the invention is an important organic molecule parent nucleus structure, can be applied to the synthesis of complex natural products, bioactive molecules or functional material molecules, and therefore has a very important position in the fields of organic synthesis and reaction diversity. In addition, the 4-azafluorene compound can also be used as an important organic synthon intermediate for synthesizing important 4-azafluorenone derivatives.
In some embodiments of the invention, R 1 Selected from the group consisting of the C1-C5 straight chain alkyl, aryl, heteroaryl, ester group, or fused aryl;
further, R 1 Selected from C1-C5 linear alkyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-naphthyl, 2-thienyl;
further, R 1 Is selected from one of phenyl, 4-chlorphenyl, 4-methylphenyl or n-butyl.
In some embodiments of the invention, R 2 Selecting the C1-C5 linear alkyl, aryl, heteroaryl, ester group or fused aryl;
further, R 2 Selected from C1-C5 linear alkyl, phenyl, 4-chlorophenyl, 4-methylphenyl, 2-naphthyl, 2-furyl;
further, R 2 Is selected from one of phenyl, 4-chlorphenyl, 2-furyl, n-propyl or methyl.
In some embodiments of the invention, R 3 Selected from 8-methoxy group,8-trifluoromethyl, 6-methoxy or hydrogen atom.
In some embodiments of the invention, R 4 One selected from methyl ester group, ethyl ester group or tert-butyl ester group;
further, R 4 Is selected from one of ethyl or tertiary butyl.
In some embodiments of the invention, the compounds of formula i include the following structures:
in a second aspect, the present invention provides a process for the preparation of a compound of formula i: the enynone compound and the isocyanoacetic ester compound are subjected to a series cyclization reaction to obtain the compound shown in the formula I.
The existing synthesis method of the 4-azafluorene compound is generally based on cyclization reaction of a 2-aryl pyridine or aryl (pyridine-3-yl) ketone derivative substrate, and the method needs to construct a five-membered ring in a tricyclic framework in advance and also needs a metal reagent, and is carried out under the condition of isolating water or oxygen, so that the reaction steps are complex, and the reaction conditions are harsh.
Compared with the prior art, the synthesis method of the 4-azafluorene compound provided by the invention has the advantages that the ketene compound and the isocyanoacetic ester compound are reacted in the organic solvent, and compared with the prior art, the method does not need to construct a five-membered ring in a tricyclic framework in advance, does not need a metal reagent, does not need to isolate water or oxygen, only needs to undergo primary intramolecular ring and form a hexahydric azayne positive ion intermediate under mild conditions of alkali catalysis, further performs intramolecular cyclization reaction, and then performs proton migration, oxidative aromatization and the like to obtain a final product.
When an electron-withdrawing group such as an ester group, a cyano group, a phosphoryl group, a sulfonyl group, or an amide group is introduced into the alpha-position of the isonitrile, the alpha-acidity is remarkably enhanced, that is: an activated methylene isonitrile compound. The compounds not only have the reactivity of isonitrile, but also have various nucleophilic reactions at alpha-position, wherein ethyl isocyanoacetate is typical active methylene isonitrile. Because of the inherent alpha-acidic characteristic and the characteristic property of an isocyano group, ethyl isocyanoacetate is often used as a 1, 3-dipole and forms a series of heterocyclic cycloaddition reactions with a polarization multiple bond, and related reports for realizing the construction of a heterocyclic compound by utilizing the 1, 3-double nucleophilicity of the isocyanoacetate do not appear so far. On the other hand, the conjugated eneynone compounds are reaction synthetic agents with high activity and multiple reaction sites, the basic structural framework of the conjugated eneynone compounds contains conjugated carbonyl, carbon-carbon double bonds (or benzene rings) and carbon-carbon triple bonds, various cyclic compounds can be constructed, and the conjugated eneynone compounds have the advantages of new reaction modes, catalytic properties, diversity, high selectivity and the like.
Therefore, the serial cyclization reaction of the isocyano acid ester compound and the conjugated eneynone provides a new method for synthesizing the polysubstituted 4-azafluorene compound. The preparation method has the advantages of mild conditions, simple and efficient operation, stable and easily obtained raw materials and reagents, no need of metal reagents, strong practicability and suitability for synthesizing various multi-substituted 4-azafluorene compounds.
Further, the reaction scheme is as follows:
wherein R is 1 、R 2 、R 3 、R 4 Is as defined above.
Further, the reaction route comprises the following steps:
1) in an organic solvent, carrying out a series cyclization reaction on isocyano acid ester and conjugated enealkynone;
2) after the reaction, removing the organic solvent from the product, and then carrying out silica gel column chromatography to obtain the 4-azafluorene compound.
In some embodiments of the invention, the conjugated enynone is selected from the group consisting of (E) -3-benzylidene-5-phenylpent-4-yn-2-one, (E) -3- (4-chlorobenzylidene) -5-phenylpent-4-yn-2-one, (E) -3- (4-methylbenzylidene) -5-phenylpent-4-yn-2-one, (E) -3- (phenylethynyl) oct-3-en-2-one, (E) -2-benzylidene-1, 4-diphenylbut-3-yn-1-one, (E) -2-benzylidene-1- (4-chlorophenyl) -4-phenylbut-3-yn-1-one, and mixtures thereof, (E) -2-benzylidene-1- (furan-2-yl) -4-phenylbut-3-yn-1-one, (E) -3-benzylidene-1-phenylhept-1-yn-4-one, (E) -2-benzylidene-4- (4-methoxyphenyl) -1-phenylbut-3-yn-1-one, (E) -2-benzylidene-4- (4-trifluoromethylphenyl) -1-phenylbut-3-yn-1-one, (E) -2-benzylidene-4- (2-methoxyphenyl) -1-phenylbut-3-yn-1-one.
In some embodiments of the invention, the isocyanoacetate is selected from ethyl isocyanoacetate, t-butyl isocyanoacetate.
In some embodiments of the invention, a catalyst is added in the reaction process, and the reaction is carried out under the action of the catalyst;
further, the catalyst is potassium tert-butoxide;
further, the mol percentage content of the catalyst is 20-50 mol%; further preferably 30 mol%.
In some embodiments of the invention, the molar ratio of conjugated eneynone to isocyanoate ester is 1: 1-2; further preferably 1: 1.2.
In some embodiments of the invention, the organic solvent is selected from 1, 4-dioxane, 1, 2-dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile; 1, 4-dioxane is preferred.
In some embodiments of the invention, 1 ml of solvent is used for each 0.2 mmol of reaction.
In some embodiments of the invention, the reaction temperature is 25-80 ℃; further, the reaction temperature was 65 ℃.
In some embodiments of the invention, the reaction time is from 1 to 12 hours; the reaction time was 8 h. The different raw materials result in shortened or prolonged time due to the difference in activity.
In a third aspect, the invention provides a pharmaceutical composition comprising a compound of formula I as described above, or an isomer or solvate or pharmaceutically acceptable molecule thereof.
The fourth aspect of the invention provides an application of a 4-azafluorene compound shown in formula I and a derivative thereof in preparation of a cervical cancer cell growth inhibitor.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1
Preparation of 4-azafluorene compound 3a
Adding (E) -3-benzylidene-5-phenylpentane-4-alkyne-2-one 1a (0.2mmol) and ethyl isocyanoacetate 2a (0.24mmol) into a 15mL pressure resistant tube, dissolving with 1mL1, 4-dioxane, adding potassium tert-butoxide (0.06mmol) as a catalyst, adding a stirrer, screwing down a pressure resistant tube cock, putting into a metal module preheated to 65 ℃ for stirring, reacting for 8h, detecting the complete disappearance of the substrate 1a by TLC, stopping the reaction, standing to room temperature, washing with a saturated ammonium chloride solution, extracting with a dichloromethane solution for three times, combining organic phase solutions, washing with a saturated sodium chloride solution once, evaporating the solvent under reduced pressure, separating by silica gel column chromatography to obtain a final product, and verifying that the product is a polysubstituted 4-azafluorene compound 3a by nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum detection, the yield thereof was found to be 73%.
FIG. 1 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 1 of the present invention, and FIG. 2 is a nuclear magnetic carbon spectrum thereof.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.97(t,J＝6.8Hz,3H),1.91(s,3H),3.95(s,2H),4.14(q,J＝6.8Hz,2H),7.33-7.36(m,2H),7.42-7.45(m,3H),7.45-7.49(m,2H),7.57-7.59(m,1H),8.19-8.21(m,1H). 13 C NMR(100MHz,CDCl 3 )δ13.5,30.7,33.8,61.6,121.8,125.1,127.4,128.5,128.6,129.3,129.4,129.6,134.3,136.2,139.4,144.0,145.4,150.1,160.5,167.2,203.1.HRMS(ESI-TOF)m/z calculated for C 23 H 20 NO 3 + ([M+H + )358.1443,found 358.1440.
Example 2
Preparation of 4-azafluorene compound 3b
The same procedures used in example 1 were repeated except for using (E) -3- (4-chlorobenzylidene) -5-phenylpent-4-yn-2-one 1b instead of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to obtain 4-azafluorene compound 3b in a yield of 68%.
1 H NMR(400MHz,CDCl 3 )δ1.06(t,J＝6.8Hz,3H),1.98(s,3H),3.94(s,2H),4.18(q,J＝6.8Hz,2H),7.28(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),7.46-7.49(m,2H),7.57-7.59(m,1H),8.18-8.21(m,1H). 13 C NMR(100MHz,CDCl 3 )δ13.6,30.9,33.8,61.7,121.9,125.1,127.5,128.1,128.9,129.8,130.7,134.3,134.7,134.9,139.2,144.0,145.5,149.9,160.9,166.8,202.7.HRMS(ESI-TOF)m/z calculated for C 23 H 19 ClNO 3 + ([M+H] + )392.1053,found 392.1047.
Example 3
Preparation of 4-azafluorene compound 3c
The same procedures used in example 1 were repeated except for using (E) -3- (4-methylbenzylidene) -5-phenylpent-4-yn-2-one 1c instead of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to obtain 4-azafluorene compound 3c in a yield of 68%.
FIG. 3 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 3 of the present invention, and FIG. 4 is a nuclear magnetic carbon spectrum thereof.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ1.03(t,J＝7.2Hz,3H),1.92(s,3H),2.41(s,3H),3.94(s,2H),4.17(q,J＝7.2Hz,2H),7.20-7.25(m,4H),7.45-7.48(m,2H),7.56-7.58(m,1H),8.18-8.20(m,1H). 13 C NMR(100MHz,CDCl 3 )δ13.6,21.2,30.7,33.8,61.5,121.8,125.1,127.4,129.2,129.3,129.4,129.5,133.1,134.3,138.5,139.5,144.0,145.4,150.2,160.3,167.3,203.2.HRMS(ESI-TOF)m/z calculated for C 24 H 22 NO 3 + ([M+H] + )372.1600,found 372.1602.
example 4
Preparation of 4-azafluorene compound 3d
The same procedures used in example 1 were repeated except for using (E) -3- (phenylethynyl) oct-3-en-2-one 1d in place of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to obtain 4-azafluorene compound 3d in 62% yield.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.91(t,J＝7.6Hz,3H),1.37(q,J＝7.6Hz,2H),1.45(t,J＝7.2Hz,3H),1.51-1.57(m,2H),2.61(s,3H),2.79(t,J＝8.4Hz,2H),3.83(s,2H),4.51(q,J＝7.2Hz,2H),7.41-7.46(m,2H).,7.54(dd,J 1 ＝6.4Hz,J 2 ＝2.0Hz,1H),8.11-8.13(m,1H). 13 C NMR(100MHz,CDCl 3 )δ13.7,14.2,22.9,29.5,31.5,33.4,34.1,61.8,121.6,125.0,127.4,129.3,129.7,133.1,139.4,143.0,147.0,149.6,158.8,167.1,203.4.HRMS(ESI-TOF)m/z calculated for C 21 H 24 NO 3 + ([M+H] + )338.1756,found 338.1738
example 5
Preparation of 4-azafluorene compound 3e
The same procedures used in example 1 were repeated except for using (E) -2-benzylidene-1, 4-diphenylbut-3-yn-1-one 1E instead of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to obtain 4-azafluorene compound 3E in a yield of 81%.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.95(t,J＝7.2Hz,3H),3.80(s,2H),4.13(q,J＝7.2Hz,2H),7.17-7.21(m,5H),7.31(t,J＝7.6Hz,2H),7.44-7.46(m,1H),7.49(td,J 1 ＝7.2Hz,J 2 ＝2.0Hz,3H),7.59-7.61(m,2H),8.25(dd,J 1 ＝7.6Hz,J 2 ＝1.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ13.5,33.5,61.6,121.9,125.1,127.5,127.9,128.0,128.6,129.3,129.4,129.6,130.7,133.9,135.2,135.7,135.8,139.4,143.8,144.4,150.0,160.0,167.3,195.5.HRMS(ESI-TOF)m/z calculated for C 28 H 22 NO 3 + ([M+H] + )420.1600,found 420.1623.
example 6
Preparation of 4-azafluorene compound 3f
The same procedures used in example 1 were repeated except for using (E) -2-benzylidene-1- (4-chlorophenyl) -4-phenylbutan-3-yn-1-one 1f in place of (E) -3-benzylidene-5-phenylpentan-4-yn-2-one 1a used in example 1 to give 4-azafluorene compound 3f in a yield of 76%.
FIG. 5 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 6 of the present invention, and FIG. 6 is a nuclear magnetic carbon spectrum thereof.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.95(t,J＝7.2Hz,3H),3.79(s,2H),4.13(q,J＝7.2Hz,2H),7.19(s,5H),7.26(dt,J 1 ＝8.8Hz,J 2 ＝2.0Hz,2H),7.43-7.47(m,1H),7.49-7.53(m,4H),8.24(dt,J 1 ＝7.6Hz,J 2 ＝1.2Hz,1H). 13 C NMR(100MHz,CDCl 3 )13.5,33.5,61.6,122.0,125.1,127.6,128.1(2C),129.0,129.4,129.8,130.5,130.6,134.1,135.2,135.5,139.3,140.5,143.8(2C),150.1,160.2,167.2,194.3.HRMS(ESI-TOF)m/z calculated for C 28 H 21 ClNO 3 + ([M+H] + )454.1210,found 454.1195.
example 7
Preparation of 3g of 4-azafluorene compound
The same procedures used in example 1 were repeated except for using 1g of (E) -2-benzylidene-1- (furan-2-yl) -4-phenylbut-3-yn-1-one in place of 1a of (E) -3-benzylidene-5-phenylpent-4-yn-2-one in example 1 to give 3g of 4-azafluorene compound in 70% yield.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.96(t,J＝7.2Hz,3H),3.90(s,2H),4.14(q,J＝7.2Hz,2H),6.41(dd,J 1 ＝3.6Hz,J 2 ＝1.6Hz,1H),6.87(d,J＝3.6Hz,1H),7.25-7.29(m,5H),7.46-7.50(m,3H),7.55(d,J＝6.4Hz,1H),8.23-8.26(m,1H). 13 C NMR(100MHz,CDCl 3 )δ13.5,33.4,61.6,112.6,120.8,121.9,125.1,127.5,128.0,128.1,129.3,129.7,130.7,135.5,135.7,139.3,143.1,143.8,147.8,150.0,151.6,160.1,167.3,182.3.HRMS(ESI-TOF)m/z calculated for C 26 H 20 NO 4 + ([M+H] + )410.1392,found 410.1387.
example 8
Preparation of 4-azafluorene compound for 3h
The same procedures used in example 1 were repeated except for using (E) -3-benzylidene-1-phenylhept-1-yn-4-one 1h in place of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to give 4-azafluorene compound in 3h, i.e., 68% yield.
FIG. 7 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 8 of the present invention, and FIG. 8 is a nuclear magnetic carbon spectrum thereof.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.65(t,J＝7.2Hz,3H),0.96(t,J＝7.6Hz,3H),1.40(f,J＝7.2Hz,2H),2.08(t,J＝7.2Hz,2H),3.91(s,2H),4.13(q,J＝7.6Hz,2H),7.31-7.35(m,2H),7.40-7.44(m,3H),7.48(td,J 1 ＝7.2Hz,J 2 ＝1.6Hz,2H),7.56-7.58(m,1H),8.19-8.21(m,1H). 13 C NMR(100MHz,CDCl 3 )δ13.4,13.5,16.9,33.6,45.1,61.5,121.8,125.1,127.4,128.4,128.5,129.3,129.4,129.6,134.3,136.1,139.4,143.9,145.7,150.0,160.3,167.2,205.9.HRMS(ESI-TOF)m/z calculated for C 25 H 24 NO 3 + ([M+H] + )386.1756,found 386.1742.
Example 9
Preparation of 4-azafluorene compound 3i
The same procedures used in example 1 were repeated except for using (E) -2-benzylidene-4- (4-methoxyphenyl) -1-phenylbut-3-yn-1-one 1i instead of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to obtain 4-azafluorene compound 3i in a yield of 51%.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.93(t,J＝7.6Hz,3H),3.71(s,2H),3.93(s,3H),4.12(q,J＝7.6Hz,2H),7.02(dd,J 1 ＝8.4Hz,J 2 ＝2.4Hz,1H),7.16-7.21(m,5H),7.30(td,J 1 ＝8.0Hz,J 2 ＝2.0Hz,2H),7.38(d,J＝8.0Hz,1H),7.47(tt,J 1 ＝8.0Hz,J 2 ＝1.2Hz,1H),7.58-.7.61(m,2H),7.75(d,J＝2.4Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ13.5,32.8,55.7,61.6,104.9,118.2,125.8,127.9,128.0,128.6,129.3,129.4,130.7,133.9,135.7,135.8,136.1,136.3,140.6,144.3,149.8,159.7,160.0,167.3,195.4.HRMS(ESI-TOF)m/z calculated for C 29 H 24 NO 4 + ([M+H] + )450.1705,found 450.1701.
example 10
Preparation of 4-azafluorene compound 3j
The same procedures used in example 1 were repeated except for using (E) -2-benzylidene-4- (4-trifluoromethylphenyl) -1-phenylbut-3-yn-1-one 1j in place of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to obtain 4-azafluorene compound 3j in a yield of 49%.
FIG. 9 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 10 of the present invention, and FIG. 10 is a nuclear magnetic carbon spectrum thereof.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.99(t,J＝7.2Hz,3H),3.88(s,2H),4.16(q,J＝7.2Hz,2H),7.18-7.23(m,5H),7.32(td,J 1 ＝8.0Hz,J 2 ＝1.6Hz,2H),7.48(tt,J 1 ＝8.0Hz,J 2 ＝1.6Hz,1H),7.60(dd,J 1 ＝8.4Hz,J 2 ＝1.6Hz,2H),7.61(d,J＝8.0Hz,1H),7.71(dd,J 1 ＝8.0Hz,J 2 ＝1.6Hz,1H),8.54(s,1H). 13 C NMR(100MHz,CDCl 3 )δ13.5,33.7,61.8,119.0(q,J＝3.9Hz),124.1(q,J＝270.7Hz),125.6,126.3(q,J＝3.6Hz),128.1(2C),128.6,129.3,129.4,130.2(q,J＝32.3Hz),131.5,134.1,135.3,135.4,135.6,140.0,144.7,147.1,150.6,158.6,167.0,195.2.HRMS(ESI-TOF)m/z calculated for C 29 H 21 F 3 NO 3 + ([M+H] + )488.1474,found 488.1461.
example 11
Preparation of 4-azafluorene compound 3k
With (E) -2-benzylidene-4- (2-methoxyphenyl) -1-phenylbut-3-yn-1-one. The same procedures used in example 1 were repeated except for using 1k instead of (E) -3-benzylidene-5-phenylpent-4-yn-2-one 1a used in example 1 to give 3k, a yield of 72%, a 4-azafluorene compound.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.94(t,J＝7.2Hz,3H),3.71(s,2H),3.87(s,3H),4.12(q,J＝7.2Hz,2H),6.95(d,J＝8.0Hz,1H),7.17-7.23(m,5H),7.31(t,J＝8.0Hz,2H),7.45-7.50(m,2H),7.60-7.62(m,2H),7.86(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ13.6,30.9,55.2,61.5,111.0,114.4,127.9,128.0,128.6,129.2,129.3,129.4,130.7,131.6,134.0,135.2,135.7(2C),140.8,144.5,149.9,156.0,160.0,167.3,195.3.HRMS(ESI-TOF)m/z calculated for C 29 H 24 NO 4 + ([M+H] + )450.1705,found 450.1700.
example 12
Preparation of 3l 4-azafluorene compound
The same procedures used in example 1 were repeated except for using tert-butyl isocyanoacetate 2b in place of ethyl isocyanoacetate 2a in example 1 to give 3l of 4-azafluorene compound in a yield of 62%.
FIG. 11 is a nuclear magnetic hydrogen spectrum of a 4-azafluorene compound obtained in example 12 of the present invention, and FIG. 12 is a nuclear magnetic carbon spectrum thereof.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ1.23(s,9H),1.90(s,3H),3.93(s,2H),7.34-7.36(m,2H),7.42-7.47(m,5H),7.56-7.57(m,1H),8.22-8.24(m,1H). 13 C NMR(100MHz,CDCl 3 )δ27.5,30.8,33.8,82.6,121.9,125.0,127.4,128.4,128.6,128.7,129.5,129.7,133.7,136.5,139.6,144.0,145.4,151.3,160.4,166.3,203.3.HRMS(ESI-TOF)m/z calculated for C 25 H 24 NO 3 + ([M+H] + )386.1756,found 386.1748.
example 13
Preparation of 4-azafluorenone compound 4a
Adding 4-acetyl-3-phenyl-5H-indeno [1,2-b ] pyridine-2-ethyl acetate 3a (0.2mmol) into a 15mL pressure resistant tube, dissolving with 1mL1, 4-dioxane, adding catalysts of potassium tert-butoxide (0.06mmol), BHT (0.4mmol) and a stirrer, screwing down a cock of the pressure resistant tube, putting into a metal module preheated to 65 ℃ for stirring, reacting for 1H, detecting the complete disappearance of the substrate 3a by TLC, stopping the reaction, standing to room temperature, washing with saturated ammonium chloride solution, extracting with dichloromethane solution for three times, combining organic phase solution, washing with saturated sodium chloride solution once, evaporating the solvent under reduced pressure, separating by silica gel column chromatography to obtain the final product, detecting by nuclear magnetic hydrogen spectrum, carbon spectrum and mass spectrum to confirm that the product is 4-acetyl-5-oxo-3-phenyl-5H-indeno [1,2-b ] pyridine-2-acetic acid ethyl ester 4a, yield 92%.
Spectrogram analysis data:
1 H NMR(400MHz,CDCl 3 )δ0.94(t,J＝7.2Hz,3H),2.22(s,3H),4.10(q,J＝7.2Hz,2H),7.26-7.28(m,2H),7.39-7.47(m,3H),7.49(td,J 1 ＝7.6Hz,J 2 ＝1.2Hz,1H),7.65(td,J 1 ＝7.6Hz,J 2 ＝1.2Hz,1H),7.74(d,J＝7.6Hz,1H),7.97(d,J＝7.6Hz,1H). 13 C NMR(100MHz,CDCl 3 )δ13.5,31.2,61.9,121.9,123.6,124.4,128.5,128.9,129.2,131.5,131.7,133.8,134.8,135.8,142.4,147.5,154.7,163.7,166.0,189.9,200.5.HRMS(ESI-TOF)m/z calculated for C 23 H 18 NO 4 + ([M+H] + )372.1236,found 372.1223.
the growth inhibitory activity of the prepared compounds 3a-3l, 4a on human cervical cancer cells (Hela) was measured.
Experimental materials: microscope for OLYMPUS cell culture, Forma TM 310 cell culture box, Thermo Scientific herapeugard ECO clean bench, Eppendorf 5910R refrigerated centrifuge, Spectra Max M5 microplate reader, panasonic MVS-83 autoclave, human cervical carcinoma cell Hela, 96 well cell culture plate, DMEM medium, PBS buffer, Gibco fetal bovine serum, 0.25% trypsin-EDTA digest, penicillin-streptomycin mixture, MTT.
The experimental method comprises the following steps:
(1) inoculating cells: a single cell suspension was prepared from a culture medium containing 10% fetal calf serum, and the suspension was seeded into a 96-well plate in a volume of 100. mu.L per well of 1000 cells per well.
(2) Culturing the cells: at 37 ℃ with 5% CO 2 Culturing in a cell culture box.
(3) Color generation: after the cells adhered to the wall, adding 3a-3L and 4a of drugs with different concentrations (0.1 μm, 0.5 μm and 1.0 μm) into each well, culturing for 24h, sucking off the cell culture solution, washing the plate with PBS 3 times, adding MTT solution (0.5mg/mL PBS) 100 μ L/well, and setting blank control as 200 μ L blank culture medium.
(4) Incubation was continued at 37 ℃ for 4 hours, and the incubation was stopped with 150. mu.L of DMSO per well and shaken for 10 minutes to allow the crystals to fully melt.
(5) On an enzyme linked immunosorbent instrument, the 490nm wavelength is selected, and the light absorption value of each hole is measured and recorded.
The calculated inhibition ratios are shown in table 1.
TABLE 1 inhibition rate of the compounds on Hela of cervical cancer cells at concentrations of 0.1. mu.M, 0.5. mu.M and 1.0. mu.M
As is clear from Table 1, each of the compounds 3a to 3l and 4a had an inhibitory activity on the growth of human cervical cancer cells. Wherein, the compounds 3a, 3b, 3c, 3e, 3f, 4j and 4a all have stronger inhibitory activity on the growth of cervical cancer cells.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A4-azafluorene compound has a structural general formula shown in formula I:
in the formula I, R is 1 Is phenyl, 4-chlorophenyl, 4-methylphenyl or n-butyl;
the R is 2 Is phenyl, 4-chlorophenyl, 2-furyl, n-propyl or methyl;
said R is 3 Is 8-methoxy, 8-trifluoromethyl, 6-methoxy or a hydrogen atom;
the R is 4 Selected from ethyl or tert-butyl.
2. The compound of claim 1, wherein: the compound shown in the formula I is one of the following structures:
3. A process for the preparation of 4-azafluorene compounds according to any one of claims 1-2, wherein: the method comprises the following steps: carrying out a series cyclization reaction on an eneynone compound and an isocyanoacetic ester compound to obtain a compound shown as a formula I;
the reaction scheme is as follows:
the preparation method comprises the following specific steps:
1) in an organic solvent, performing series cyclization reaction on isocyanoacetate and conjugated enealkynone;
2) after the reaction, removing the organic solvent from the product, and then carrying out silica gel column chromatography to obtain a 4-azafluorene compound;
the conjugated eneynone is selected from (E) -3-benzylidene-5-phenylpent-4-yn-2-one, (E) -3- (4-chlorobenzylidene) -5-phenylpent-4-yn-2-one, (E) -3- (4-methylbenzylidene) -5-phenylpent-4-yn-2-one, (E) -3- (phenylethynyl) oct-3-en-2-one, (E) -2-benzylidene-1, 4-diphenylbut-3-yn-1-one, (E) -2-benzylidene-1- (4-chlorophenyl) -4-phenylbut-3-yn-1-one, and mixtures thereof, (E) -2-benzylidene-1- (furan-2-yl) -4-phenylbut-3-yn-1-one, (E) -3-benzylidene-1-phenylhept-1-yn-4-one, (E) -2-benzylidene-4- (4-methoxyphenyl) -1-phenylbut-3-yn-1-one, (E) -2-benzylidene-4- (4-trifluoromethylphenyl) -1-phenylbut-3-yn-1-one, (E) -2-benzylidene-4- (2-methoxyphenyl) -1-phenylbut-3-yn-1-one;
The isocyanoacetate is selected from ethyl isocyanoacetate and tert-butyl isocyanoacetate;
the molar ratio of the conjugated eneynone to the isocyanoacetic ester is 1: 1-2;
adding a catalyst in the reaction process, and reacting under the action of the catalyst;
the catalyst is potassium tert-butoxide;
the mole percentage of the catalyst is 20-50 mol%;
the organic solvent is selected from 1, 4-dioxane, 1, 2-dichloromethane, tetrahydrofuran, ethyl acetate and acetonitrile;
1 ml of solvent was used for each 0.2 mmol reaction;
the reaction temperature is 25-80 ℃;
the reaction time is 1-12 h.
4. The method of claim 3, wherein: the molar percentage of the catalyst is 30 mol%.
5. The method of claim 3, wherein: the molar ratio of conjugated eneynone to isocyanoacetate was 1: 1.2.
6. The method of claim 3, wherein: the organic solvent is 1, 4-dioxane.
7. The method of claim 3, wherein: the reaction temperature was 65 ℃.
8. The method of claim 3, wherein: the reaction time was 8 h.
9. A pharmaceutical composition characterized by: comprising a 4-azafluorene compound according to any one of claims 1-2.
10. Use of the 4-azafluorene compound of any one of claims 1-2 for the preparation of a cervical cancer cell growth inhibitor.
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| JP2001139556A (en) * | 1999-03-18 | 2001-05-22 | Nippon Soda Co Ltd | Indenopyridine and indenopyrimidine compound and method for producing the same |
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