CN112079777B - Polysubstituted 4-fluoroacridine derivative and preparation method thereof - Google Patents
Polysubstituted 4-fluoroacridine derivative and preparation method thereof Download PDFInfo
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Abstract
The invention provides a polysubstituted 4-fluoroacridine derivative and a preparation method thereof. The polysubstituted 4-fluoroacridine derivative has a structure shown in a formula (I):
wherein R is1Is alkyl, alkoxy, cycloalkyl, aryl, ester group, ether group, heterocyclic group or halogen; r2～R4Independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, ester, ether, heterocyclic or halogen; r2Represents a substituent at any position on the benzene ring, R2The number of substitution of (a) is 1 to 4, and the ortho position of the phenyl ring amino group is not simultaneously substituted by R2Substitution; r3And R4Are individual substituents or are linked to form a cycloalkyl radical; EWG is an electron withdrawing group. The polysubstituted 4-fluoroacridine derivative provided by the invention has a rigid planar structure and good biological activity, and can be widely applied to the fields of photoelectric materials, chemical analysis, anti-cancer, anti-bacterial, insect-expelling, antimalarial and other medicines.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a polysubstituted 4-fluoroacridine derivative and a preparation method thereof.
Background
The acridine compound is an important fused heterocyclic organic compound, has a rigid plane structure due to a macrocyclic conjugated system, has extremely strong fluorescence performance, is a good fluorescent reagent, and is widely applied to the field of photoelectric materials. For example, 9-phenylacridine is an important acridine structural molecule, can be used as a photoinitiator and a sensitizer to initiate a photoinitiator to carry out photopolymerization, can also be used as a photoinitiator in a photopolymerization system, and is an important component of a UV (ultraviolet) photocuring system. In addition, the acridine compound has good biological activity and is widely applied to the fields of chemical analysis and medicaments for resisting cancers, bacteria, insects, malaria and the like. Meanwhile, by introducing fluorine atoms with high electronegativity into molecules, the electron cloud distribution, the acidity and basicity, the dipole moment and the lipophilic property of the original molecules can be greatly changed, so that the physical and chemical properties of the molecules are remarkably changed.
Industrial synthesis of acridine compounds is mainly carried out by bernstsen method (org. lett.,2000,18,833), using diarylamine and carboxylic acid or anhydride as raw materials, and co-heating under the catalysis of composite catalyst composed of zinc chloride and polyphosphoric acid to generate 9-substituted acridine derivatives. However, the method has a great corrosion effect on a reaction kettle due to the reaction under the conditions of high temperature and polyphosphoric acid, and generates a large amount of zinc salt solid waste residues, thereby causing certain pollution to the environment. There are a number of small-scale laboratory procedures for preparing acridine compounds, but most strategies are to generate pyridine building blocks in the acridine ring by cyclization (eur.j. org.chem.,2017,3, 577.). There are also a few reports of acridine formation by cyclization of quinoline derivatives (chem.
Therefore, the method for synthesizing the acridine compound by one-step construction of the benzene ring and the acridine ring structure under the green, mild and good practical reaction conditions has important research significance and application value.
Disclosure of Invention
The invention aims to overcome the defect or deficiency that the existing acridine compounds are difficult to prepare, and provides a polysubstituted 4-fluoroacridine derivative. The polysubstituted 4-fluoroacridine derivative provided by the invention is an acridine structure skeleton, and can be widely applied to the fields of photoelectric materials, chemical analysis, anti-cancer, antibacterial, insect-expelling, antimalarial and other medicines due to the rigid planar structure and good biological activity.
Another object of the present invention is to provide a process for producing the polysubstituted 4-fluoroacridine derivative.
The invention also aims to provide the application of the polysubstituted 4-fluoroacridine derivative in the fields of preparation of photoinitiators, sensitizers, preparation of anti-cancer, antibacterial, anthelmintic or antimalarial drugs or chemical analysis.
In order to achieve the purpose, the invention adopts the following technical scheme:
a polysubstituted 4-fluoroacridine derivative has a structure shown in formula (I):
wherein R is1Is alkyl, alkoxy, cycloalkyl, aryl, ester group, ether group, heterocyclic group or halogen;
R2～R4independently selected from hydrogen, alkyl, alkoxy, cycloalkyl, aryl, esterA group, ether group, heterocyclic group or halogen;
R2represents a substituent at any position on the benzene ring, R2The number of substitution of (a) is 1 to 4, and the ortho position of the phenyl ring amino group is not simultaneously substituted by R2Substitution; r is3And R4Are separate substituents or are linked to form a cycloalkyl group; EWG is an electron withdrawing group.
The polysubstituted 4-fluoroacridine derivative provided by the invention has a rigid planar structure and good biological activity, and can be widely applied to the fields of photoelectric materials, chemical analysis, anti-cancer, anti-bacterial, insect-expelling, antimalarial and other medicines.
And the polysubstituted 4-fluoroacridine derivative is easy to prepare and has good application prospect.
Preferably, the alkyl group is C1～10An alkyl group. Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl and the like; more preferably C1～4Alkyl groups, particularly preferably methyl, ethyl and propyl.
Preferably, the alkoxy group is C1～10An alkoxy group. Such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy and the like; more preferably C1～4An alkoxy group; particularly preferred are methoxy, ethoxy and isopropoxy.
Preferably, said cycloalkyl is C5～8A cycloalkyl group of (a).
Preferably, the aryl group is phenyl or substituted phenyl. The substituents may be one or more, and the positions may be ortho, para and meta. As the substituent of the phenyl group, a general substituent such as an alkyl group, an alkoxy group, a trifluoromethyl group, an alkenyl group, an aryl group, an ester group, a nitro group, a hydroxyl group, a halogen group or the like may be mentioned.
Preferably, the ester group is an alkyl or aryl formate group.
Preferably, the ether group is methoxy, ethoxy or isopropoxy.
Preferably, the heterocyclic group is thienyl, furyl, pyridyl, thiazolyl, oxazolyl.
Preferably, the halogen is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The EWG may be a conventional electron withdrawing group.
Preferably, the EWG is an ester group or an acyl group.
More preferably, the acyl group is an arylacyl group.
More preferably, the ester group is an alkyl formate group or an aryl formate group.
Preferably, R1Independently selected from alkoxy, cycloalkyl, phenyl, alkylbenzene, alkoxybenzene, halophenyl, polycyclic aryl, ester, heterocyclic or ether groups.
Preferably, R2～R4Independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group.
The preparation method of the polysubstituted 4-fluoroacridine derivative comprises the following steps: using a photosensitizer as a catalyst, under the condition of visible light, carrying out free radical domino cyclization reaction on a halogenated difluoromethyl alkyne imine compound shown in a formula (II) and an alkenyl diazo compound shown in a formula (III), and then removing hydrogen fluoride under the alkaline condition to obtain the 4-fluoroacridine derivative;
the preparation method provided by the invention selects non-cyclic raw materials, and pyridine and benzene ring units in acridine are constructed in one step through the continuous addition cyclization reaction of free radicals. Compared with the traditional method, the method of the invention uses visible light driving force, the reaction condition is mild, and the practicability is better; in addition, the halogenated difluoromethyl alkyne imine compound and the alkenyl diazo compound are simple and easy to obtain; meanwhile, the method has good substrate universality, simple reaction operation, high yield, easy separation and purification of products and good application prospect.
Photosensitizers conventional in the art may be used in the present invention, also in conventional amounts.
Preferably, the photosensitizer is one or more of ruthenium terpyridyl chloride, ruthenium tris-phenanthroline chloride, iridium tris (2-phenylpyridine) complex, fluorescein, rose bengal, eosin Y or methyl blue.
Preferably, the dosage of the photosensitizer is 1% of the molar dosage of the halogenated difluoromethyl alkyne imine compound.
Preferably, the molar ratio of the halogenated difluoromethyl alkyne imine compound to the alkenyl diazo compound is 1: 1-1: 5.
Preferably, the free-radical domino cyclization reaction is carried out under the following conditions: taking an organic solvent as a medium, and reacting for 6-72 hours at 0-80 ℃ under an alkaline condition.
More preferably, the organic solvent is one or more of dichloromethane, dichloroethane, ethyl acetate, ethanol, methanol, isopropanol, acetonitrile, dioxane, tetrahydrofuran, toluene or chlorobenzene.
These solvents have the advantage of being inexpensive and readily available.
More preferably, the alkaline conditions are obtained by the addition of an inorganic or organic base.
Inorganic bases or organic bases conventional in the art may be used in the present invention.
Specifically, the inorganic base is one or more of sodium carbonate, potassium bicarbonate, disodium hydrogen phosphate, sodium phosphate, potassium phosphate or dipotassium hydrogen phosphate.
Specifically, the organic base is one or more of tri-n-butylamine, triethylamine, diisopropylethylamine or diethylamine.
Preferably, the free radical domino cyclization reaction further comprises a step of adding an electron donor compound into the reaction system.
More preferably, the electron donor compound is one or more of tri-n-butylamine, triethylamine, diisopropylethylamine or diethylamine.
More preferably, the dosage of the electron donor compound is 1-100% of the mass of the halogenated difluoromethyl alkyne imine compound
Light sources that provide visible light that are conventional in the art may be used in the present invention.
Preferably, blue light of the LED is selected as the light source.
The polysubstituted 4-fluoroacridine derivative is applied to the fields of preparing photoinitiators, sensitizing agents, preparing anti-cancer, antibacterial, insect-repellent or antimalarial drugs or chemical analysis.
Compared with the prior art, the invention has the following beneficial effects:
(1) the polysubstituted 4-fluoroacridine derivative provided by the invention has a rigid planar structure and good biological activity, and can be widely applied to the fields of photoelectric materials, chemical analysis, anti-cancer, anti-bacterial, insect-expelling, antimalarial and other medicines.
(2) The preparation method provided by the invention selects non-cyclic raw materials, and pyridine and benzene ring units in acridine are constructed in one step through the continuous addition cyclization reaction of free radicals. Compared with the traditional method, the method of the invention uses visible light driving force, the reaction condition is mild, and the practicability is better; in addition, the halogenated difluoromethyl alkyne imine compound and the alkenyl diazo compound are simple and easy to obtain; meanwhile, the method has good substrate universality, simple reaction operation, high yield, easy separation and purification of products and good application prospect.
Detailed Description
The invention is further illustrated by the following examples. These examples are intended to illustrate the invention and are not intended to limit the scope of the invention. Experimental procedures without specific conditions noted in the examples below, generally according to conditions conventional in the art or as suggested by the manufacturer; the reactants, reagents and the like used are, unless otherwise specified, those commercially available from the conventional market and the like. Any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
The general formula for synthesizing the polysubstituted 4-fluoroacridine derivative in each embodiment of the invention is as follows:
the method comprises the following specific steps: adding 1 part of halogenated difluoromethyl alkyne imine formula (II), 1-5 parts of alkenyl diazo reagent formula (III), 0.1-1 part of electron donor, 2-5 parts of alkali and 0.01 part of photocatalyst into a proper amount of organic solvent, illuminating for 6-72 hours in a sealed reaction test tube under nitrogen atmosphere, concentrating the reaction solution, and performing column chromatography purification by using a mixed solvent of petroleum ether/ethyl acetate 5:1 as an eluent to obtain the polysubstituted 4-fluoroacridine compound formula (I).
The parts are molar parts.
EXAMPLE 11 Synthesis of ethyl ester-9-phenyl-4-fluoroacridine
1 part of chlorodifluoromethyl alkyne imine (R) is added into a microwave reaction tube1＝Ph，R2H, X-Cl), 3 parts of ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 0.1 part of triethylamine, 5 parts of potassium carbonate, 0.01 part of triphenanthroline ruthenium chloride and a proper amount of dichloromethane, sealing a reaction test tube, irradiating and stirring the reaction tube by using a 18W household fluorescent lamp at 60 ℃ in a nitrogen atmosphere for 25 hours, concentrating the reaction solution, and purifying the reaction solution by using a petroleum ether/ethyl acetate (5: 1) mixed solvent as an eluent column chromatography to obtain the 1-ethyl ester-9-phenyl-4-fluoroacridine with the yield of 79%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.7Hz,1H),7.84–7.74(m,2H),7.60–7.38(m,8H),3.57(q,J＝7.2Hz,2H),1.14(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.3,159.1(d,J＝262.3Hz),148.5,146.8(d,J＝2.7Hz),140.1(d,J＝12.3Hz),136.3,131.3,130.9,130.2,129.0(d,J＝5.5Hz),128.7,128.1,127.6(d,J＝8.7Hz),127.2,126.8,126.4,123.3,111.0(d,J＝20.0Hz),61.4,13.9。
19F NMR(376MHz,CDCl3)δ-118.9。
HRMS(APCI):calcd.for C22H17FNO2[M+H]+:346.12378,Found:346.12366。
example 21 Synthesis of ethyl ester-9- (p-tolyl) -4-fluoroacridine
Adding 1 part of bromodifluoromethyl alkyne imine (R) into a microwave reaction tube1＝p-MeC6H4，R2H, X-Br), 1 part ethyl alkenyl diazoacetate (R)3＝H,R4＝H,EWG＝CO2Et), 0.5 part of triethylamine, 2 parts of potassium phosphate, 0.01 part of tris (2-phenylpyridine) iridium complex and a proper amount of acetonitrile, sealing the reaction tube, irradiating and stirring the reaction tube with 5W LED blue light at room temperature in a nitrogen atmosphere, concentrating the reaction solution, and performing column chromatography purification by using a mixed solvent of petroleum ether and ethyl acetate (5: 1) as an eluent to obtain the 1-ethyl ester-9- (p-tolyl) -4-fluoroacridine with the yield of 78%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.37(dd,J＝9.0,0.9Hz,1H),7.85–7.78(m,2H),7.57(dd,J＝7.7,5.3Hz,1H),7.49(ddd,J＝8.6,6.7,1.2Hz,1H),7.45–7.29(m,5H),3.59(q,J＝7.2Hz,2H),2.49(s,3H),1.15(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.4,159.2(d,J＝262.2Hz),148.6,147.2(d,J＝2.8Hz),140.2(d,J＝12.3Hz),138.7,133.5,131.3,130.9,130.2,129.2(d,J＝5.5Hz),128.8,127.5(d,J＝8.7Hz),127.2,127.0,126.6,111.0(d,J＝20.0Hz),61.4,21.5,13.9。
19F NMR(376MHz,CDCl3)δ-119.0。
HRMS(APCI):calcd.for C23H19FNO2[M+H]+:360.13943,Found:360.13907。
example 31 Synthesis of ethyl ester-9- (p-fluorophenyl) -4-fluoroacridine
Adding 1 part of iodine difluoromethyl alkyne imine (R) into a microwave reaction tube1＝p-FC6H4，R2H, X ═ I), 5 parts ethyl alkenyl diazoacetate (R)3＝H,R4＝H,EWG＝CO2Et), 1 part of triethylamine, 2 parts of sodium carbonate, 0.01 part of eosin Y and a proper amount of acetonitrile, sealing a reaction test tube, irradiating and stirring the reaction tube by using sunlight at room temperature in a nitrogen atmosphere for 72 hours, concentrating the reaction solution, and performing column chromatography purification by using a mixed solvent of petroleum ether/ethyl acetate 5:1 as an eluent to obtain the 1-carbethoxy-9- (p-fluorophenyl) -4-fluoroacridine with the yield of 76%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.7Hz,1H),7.86–7.80(m,1H),7.73(d,J＝8.5Hz,1H),7.59(dd,J＝7.7,5.3Hz,1H),7.51(ddd,J＝8.8,6.6,1.2Hz,1H),7.45–7.39(m,3H),7.29–7.23(m,2H),3.69(q,J＝7.2Hz,2H),1.18(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.1,162.9(d,J＝249.2Hz),159.1(d,J＝262.6Hz),148.4,145.6(d,J＝2.8Hz),140.0(d,J＝12.4Hz),133.0,133.0,132.2(d,J＝3.5Hz),130.9,130.2,128.7(d,J＝5.5Hz),127.7,127.4,126.4,123.3,115.2(d,J＝21.6Hz),111.0(d,J＝20.1Hz),61.4,13.9。
19F NMR(376MHz,CDCl3)δ-112.4,-118.6。
HRMS(APCI):calcd.for C22H16F2NO2[M+H]+:364.11436,Found:364.11404。
EXAMPLE 41 Synthesis of carbethoxy-9- (p-chlorophenyl) -4-fluoroacridine
Adding 1 part of bromodifluoromethyl alkyne imine (R) into a microwave reaction tube1＝p-ClC6H4，R2H, X-Br), 4 parts ethyl alkenyldiazoacetate(R3＝H，R4＝H，EWG＝CO2Et), 1 part of tri-n-butylamine, 0.01 part of eosin B and a proper amount of acetonitrile, sealing a reaction tube, irradiating and stirring the reaction tube with 20W LED green light at room temperature in a nitrogen atmosphere for 6 hours, concentrating the reaction solution, and performing column chromatography purification by using a petroleum ether/ethyl acetate 5:1 mixed solvent as an eluent to obtain the 1-carbethoxy-9- (p-chlorophenyl) -4-fluoroacridine with the yield of 78%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.7Hz,1H),7.86–7.80(m,1H),7.73(d,J＝8.5Hz,1H),7.59(dd,J＝7.7,5.3Hz,1H),7.51(ddd,J＝8.8,6.6,1.2Hz,1H),7.45–7.39(m,3H),7.29–7.23(m,2H),3.69(q,J＝7.2Hz,2H),1.18(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.1,162.9(d,J＝249.2Hz),159.1(d,J＝262.6Hz),148.4,145.6(d,J＝2.8Hz),140.0(d,J＝12.4Hz),133.0,133.0,132.2(d,J＝3.5Hz),130.9,130.2,128.7(d,J＝5.5Hz),127.7,127.4,126.4,123.3,115.2(d,J＝21.6Hz),111.0(d,J＝20.1Hz),61.4,13.9。
19F NMR(376MHz,CDCl3)δ-112.4,-118.6。
HRMS(APCI):calcd.for C22H16F2NO2[M+H]+:364.11436,Found:364.11404。
EXAMPLE 51 Synthesis of ethyl ester-9- (p-bromophenyl) -4-fluoroacridine
1 part of chlorodifluoromethyl alkynimine (R) is added into a microwave reaction tube1＝p-BrC6H4，R2H, X ═ Cl), 4 parts ethyl alkenyl diazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 4 parts of triisopropylamine, 0.01 part of methylene blue and an appropriate amount of toluene, sealing the reaction tube, and irradiating and stirring the reaction tube with 30W LED blue light at room temperature in a nitrogen atmosphere to reactAfter 36h, the reaction solution is concentrated, and the mixed solvent of petroleum ether/ethyl acetate 5:1 is used as eluent for column chromatography purification, so that the 1-ethyl ester-9- (p-bromophenyl) -4-fluoroacridine is obtained, wherein the yield is 73%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.39(d,J＝8.7Hz,1H),7.87–7.81(m,1H),7.77–7.67(m,3H),7.60(dd,J＝7.7,5.3Hz,1H),7.52(ddd,J＝8.8,6.6,1.1Hz,1H),7.42(dd,J＝9.6,7.8Hz,1H),7.34–7.29(m,2H),3.69(q,J＝7.2Hz,2H),1.19(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.1,159.2(d,J＝262.8Hz),148.6,145.4,140.1(d,J＝12.4Hz),135.3,132.9,131.4,131.1,130.4,128.7(d,J＝5.7Hz),128.0(d,J＝8.7Hz),127.6,126.4,126.1,123.2,111.2(d,J＝20.1Hz),61.6,14.0。
19F NMR(376MHz,CDCl3)δ-118.5。
HRMS(APCI):calcd.for C22H16BrFNO2[M+H]+:424.03430,Found:424.03406。
EXAMPLE 61 Synthesis of carbethoxy-9- (p-methoxyphenyl) -4-fluoroacridine
Adding 1 part of bromodifluoromethyl alkyne imine (R) into a microwave reaction tube1＝p-MeOC6H4，R2H, X, Br), 2 parts of ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 0.2 part of diisopropylamine, 3 parts of cesium carbonate, 0.01 part of rose bengal and a proper amount of tetrahydrofuran, sealing a reaction test tube, irradiating and stirring the reaction tube by using 5W LED blue light at room temperature in a nitrogen atmosphere, concentrating the reaction solution, and performing column chromatography purification by using a mixed solvent of petroleum ether and ethyl acetate (5: 1) as an eluent to obtain the 1-ethyl ester-9- (p-methoxyphenyl) -4-fluoroacridine with the yield of 52%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.37(d,J＝9.0Hz,1H),7.86–7.78(m,2H),7.57(dd,J＝7.7,5.3Hz,1H),7.53–7.46(m,1H),7.44–7.31(m,3H),7.12–7.05(m,2H),3.92(s,3H),3.66(q,J＝7.2Hz,2H),1.16(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.4,160.0,159.2(d,J＝262.1Hz),148.6,146.9(d,J＝2.7Hz),140.2(d,J＝12.3Hz),132.6,130.9,130.2,129.2(d,J＝5.5Hz),128.7,127.4(d,J＝8.7Hz),127.1,126.9,126.8,123.8,113.6,111.0(d,J＝20.1Hz),61.4,55.6,14.0。
19F NMR(376MHz,CDCl3)δ-119.1。
HRMS(APCI):calcd.for C23H19FNO3[M+H]+:376.13435,Found:376.13449。
EXAMPLE 71 Synthesis of carbethoxy-9- (p-nitrophenyl) -4-fluoroacridine
1 part of iododifluoromethyl alkynimine (R) is added into a microwave reaction tube1＝p-NO2C6H4，R2H, X ═ I), 3 parts ethyl alkenyl diazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 0.01 part of riboflavin and a proper amount of ethyl acetate, sealing a reaction test tube, irradiating and stirring by using a 15W LED white light at room temperature in a nitrogen atmosphere for 15 hours, concentrating the reaction liquid, and performing column chromatography purification by using a mixed solvent of petroleum ether/ethyl acetate (5: 1) as an eluent to obtain the 1-carbethoxy-9- (p-nitrophenyl) -4-fluoroacridine with the yield of 37%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.45–8.38(m,3H),7.91–7.84(m,1H),7.70–7.60(m,4H),7.56(ddd,J＝8.9,6.5,1.2Hz,1H),7.46(dd,J＝9.5,7.8Hz,1H),3.63(q,J＝7.2Hz,2H),1.17(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ167.6,159.3(d,J＝263.6Hz),148.4,147.9,143.7,143.2,139.9(d,J＝12.4Hz),132.2,131.2,130.5,128.7(d,J＝8.9Hz),128.1,127.9(d,J＝5.8Hz),125.6,125.5,123.2,122.6,111.3(d,J＝20.0Hz),61.5,13.8。
19F NMR(376MHz,CDCl3)δ-117.6。
HRMS(APCI):calcd.for C22H16FN2O4[M+H]+:391.10886,Found:391.10831。
example 81 Synthesis of ethoxycarbonyl-9- (4-biphenyl) -4-fluoroacridine
Adding 1 part of chlorodifluoromethyl alkyne imine (R) into a microwave reaction tube1＝p-PhC6H4，R2H, X ═ Cl), 5 parts ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 0.5 part of diisopropylethylamine, 2 parts of potassium hydrogen phosphate, 0.01 part of terpyridyl ruthenium chloride and a proper amount of chlorobenzene, sealing a reaction test tube, irradiating and stirring the reaction tube by using 30W LED blue light at room temperature in a nitrogen atmosphere for 8 hours, concentrating the reaction solution, and purifying the reaction solution by using a petroleum ether/ethyl acetate (5: 1) mixed solvent as an eluent column chromatography to obtain the 1-ethyl ester-9- (4-biphenyl) -4-fluoroacridine with the yield of 71%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.40(d,J＝8.7Hz,1H),7.90–7.76(m,4H),7.75–7.69(m,2H),7.60(dd,J＝7.7,5.3Hz,1H),7.56–7.49(m,5H),7.47–7.40(m,2H),3.60(q,J＝7.2Hz,2H),1.13(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.4,159.3(d,J＝262.3Hz),148.6,146.7,141.6,140.4,140.2(d,J＝12.3Hz),131.9,131.0,130.3,129.2,128.0,127.7(d,J＝8.7Hz),127.4,127.2,126.9,126.8,126.5,123.5,111.2(d,J＝20.2Hz),61.5,14.0。
19F NMR(376MHz,CDCl3)δ-118.8。
HRMS(APCI):calcd.for C28H21FNO2[M+H]+:422.15508,Found:422.15454。
EXAMPLE 91 Synthesis of ethoxycarbonyl-9- (o-fluorophenyl) -4-fluoroacridine
Adding 1 part of bromodifluoromethyl alkyne imine (R) into a microwave reaction tube1＝o-FC6H4，R2H, X ═ Cl), 1 part ethyl alkenyl diazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 4 parts of diethylamine, 0.01 part of tris (2-phenyl-4-fluoropyridine) iridium complex and a proper amount of ethanol, sealing a reaction tube, irradiating and stirring the reaction tube by using 1W LED blue light at room temperature in a nitrogen atmosphere, reacting for 60 hours, concentrating the reaction solution, and purifying by using a petroleum ether/ethyl acetate (5: 1) mixed solvent as an eluent column chromatography to obtain the 1-ethyl ester-9- (o-fluorophenyl) -4-fluoroacridine with the yield of 75%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.39(d,J＝8.8Hz,1H),7.87–7.80(m,1H),7.68–7.50(m,4H),7.46–7.39(m,1H),7.35–7.22(m,3H),3.74–3.55(m,2H),1.16(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.2,160.2(d,J＝248.0Hz),159.3(d,J＝261.0Hz),148.4,140.74(d,J＝3.0Hz),140.1(d,J＝12.5Hz),132.7(d,J＝2.8Hz),131.3(d,J＝8.0Hz),131.1,130.4,128.6(d,J＝5.7Hz),127.9(d,J＝8.8Hz),127.8,126.3,124.3,124.2(d,J＝3.2Hz),123.7,115.8(d,J＝21.5Hz),111.2(d,J＝20.2Hz),61.5,13.8。
19F NMR(376MHz,CDCl3)δ-110.3,-118.5。
HRMS(APCI):calcd.for C22H16F2NO2[M+H]+:364.11436,Found:364.11426。
EXAMPLE 101 Synthesis of carbethoxy-9- (m-methylphenyl) -4-fluoroacridine
Adding 1 part of chlorodifluoromethyl alkyne imine (R) into a microwave reaction tube1＝m-MeC6H4，R2H, X ═ Cl), 1 part ethyl alkenyl diazoacetate (R)3＝H，R4＝H，EWG＝CO2Et), 2 parts of diisopropylamine, 0.01 part of terpyridyl ruthenium chloride and a proper amount of 1, 4-dioxane, sealing a reaction tube, irradiating and stirring by using a 24W LED white light at room temperature in a nitrogen atmosphere for 60 hours, concentrating the reaction liquid, and purifying by using a petroleum ether/ethyl acetate (5: 1) mixed solvent as an eluent column chromatography to obtain the 1-ethyl ester-9- (m-methylphenyl) -4-fluoroacridine with the yield of 78%. The structure is as follows:
compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.9Hz,1H),7.85–7.78(m,2H),7.57(dd,J＝7.7,5.3Hz,1H),7.45(ddd,J＝17.2,11.8,7.6Hz,3H),7.33(d,J＝7.6Hz,1H),7.28(d,J＝8.9Hz,1H),7.21(s,1H),3.57(qq,J＝10.8,7.2Hz,2H),2.45(s,3H),1.14(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.4,159.2(d,J＝262.2Hz),148.6,147.1(d,J＝2.7Hz),140.1(d,J＝12.3Hz),137.8,136.2,131.9,130.9,130.2,129.4,129.2(d,J＝5.7Hz),128.6,128.1,127.5(d,J＝8.7Hz),127.2,127.0,126.4,123.3,111.0(d,J＝20.0Hz),61.3,21.5,13.9。
19F NMR(376MHz,CDCl3)δ-119.0。
HRMS(APCI):calcd.for C23H19FNO2[M+H]+:360.13943,Found:360.13901。
the invention also synthesizes the following compounds, according to the procedures described in example 1:
EXAMPLE 111 Synthesis of carbethoxy-9- (p-ethynylphenyl) -4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝p-C2HC6H4，R2H, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 70%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.39(d,J＝8.7Hz,1H),7.87–7.80(m,1H),7.74(d,J＝8.7Hz,1H),7.71–7.55(m,3H),7.51(ddd,J＝8.7,6.6,1.0Hz,1H),7.47–7.39(m,3H),3.64(q,J＝7.2Hz,2H),3.21(s,1H),1.17(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.2,159.3(d,J＝262.7Hz),148.6,145.9,140.1(d,J＝12.4Hz),137.0,131.9,131.4,131.1,130.4,128.8(d,J＝5.6Hz),128.0(d,J＝8.8Hz),127.6,126.5,126.1,122.8,111.2(d,J＝20.0Hz),83.2,78.8,61.6,14.0。
19F NMR(376MHz,CDCl3)δ-118.5。
HRMS(APCI):calcd.for C24H17FNO2[M+H]+:370.12378,Found:370.12338。
example 121 Synthesis of ethoxycarbonyl-9- (1-naphthyl) -4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝1-naphthyl，R2H, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 73%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.42(d,J＝8.8Hz,1H),8.07–7.95(m,2H),7.83–7.76(m,1H),7.61(dd,J＝8.2,7.1Hz,1H),7.55–7.39(m,4H),7.36–7.24(m,4H),3.37(dq,J＝10.8,7.2Hz,1H),2.53(dq,J＝10.8,7.2Hz,1H),0.65(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.5,159.2(d,J＝261.8Hz),148.4,145.4(d,J＝2.8Hz),140.3(d,J＝12.1Hz),133.7,133.2(d,J＝9.5Hz),131.1,130.3,129.9,129.6,129.4(d,J＝5.7Hz),128.4,127.4,127.3,127.3,127.1(d,J＝9.0Hz),127.0,126.9,126.5,125.3,124.2,111.3(d,J＝20.1Hz),61.1,13.3。
19F NMR(376MHz,CDCl3)δ-118.9。
HRMS(APCI):calcd.for C26H19FNO2[M+H]+:396.13943,Found:396.13876。
example 131 Synthesis of ethyl ester-9- (3-thienyl) -4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝3-thienyl，R2H, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 78%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.7Hz,1H),7.88(d,J＝8.8Hz,1H),7.80(t,J＝7.6Hz,1H),7.64–7.55(m,2H),7.51(t,J＝7.7Hz,1H),7.45–7.30(m,3H),3.82(d,J＝6.6Hz,2H),1.22(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.0,159.1(d,J＝262.5Hz),148.4,142.0(d,J＝2.8Hz),140.1(d,J＝12.4Hz),136.8,130.9,130.7,130.2,128.9(d,J＝5.6Hz),127.8(d,J＝8.7Hz),127.3,126.9,126.6,126.5,125.6,124.1,111.0(d,J＝20.1Hz),61.5,14.1。
19F NMR(376MHz,CDCl3)δ-118.8。
HRMS(APCI):calcd.for C20H15FNO2S[M+H]+:352.08020,Found:352.08051。
EXAMPLE 141 Synthesis of ethoxycarbonyl-9- (cyclopropyl) -4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝cyclopropyl，R2H, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 43%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.67(d,J＝8.7Hz,1H),8.32(d,J＝8.7Hz,1H),7.91–7.78(m,2H),7.70–7.60(m,1H),7.35(dd,J＝9.6,7.8Hz,1H),4.46(q,J＝7.2Hz,2H),2.77–2.67(m,1H),1.45(t,J＝7.2Hz,3H),1.29–1.19(m,2H),0.54(q,J＝5.9Hz,2H)。
13C NMR(100MHz,CDCl3)δ168.8,160.1(d,J＝263.6Hz),148.4,148.3(d,J＝2.6Hz),140.2(d,J＝12.5Hz),130.8,130.4,128.8(d,J＝4.2Hz),128.7,127.8(d,J＝5.4Hz),126.9,126.3,125.4,110.5(d,J＝20.1Hz),61.64,15.7,14.4,9.7。
19F NMR(376MHz,CDCl3)δ-117.4。
HRMS(APCI):calcd.for C19H17FNO2[M+H]+:310.12378,Found:310.12328。
example 151 Synthesis of ethyl ester-7-bromo-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝C6H5Para R of phenyl ring amino2Br, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 71%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.57(d,J＝1.9Hz,1H),7.65–7.50(m,6H),7.46–7.39(m,3H),3.57(q,J＝7.2Hz,2H),1.14(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.1,159.0(d,J＝262.8Hz),148.7,147.4(d,J＝2.7Hz),140.6(d,J＝12.4Hz),135.9,132.1,131.2,130.9,129.2(d,J＝5.7Hz),129.0,128.3,128.0(d,J＝8.7Hz),125.9,125.0,123.4,111.8(d,J＝20.0Hz),61.5,13.9。
19F NMR(376MHz,CDCl3)δ-118.6。
HRMS(APCI):calcd.for C22H16BrFNO2[M+H]+:424.03430,Found:424.03339。
example 161 Synthesis of ethylcarbonyl-7-methoxy-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝C6H5Para R of phenyl ring amino2OMe, X-Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) was synthesized by the method of example 1 using Et) as a starting materialA compound having the structure:
the yield was 49%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ7.66–7.59(m,2H),7.58–7.48(m,4H),7.45–7.37(m,3H),7.15(dd,J＝9.6,2.6Hz,1H),4.02(s,3H),3.56(q,J＝7.2Hz,2H),1.13(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.5,162.0,158.9(d,J＝260.7Hz),150.6,146.6,140.3(d,J＝11.8Hz),136.5,131.3,129.2(d,J＝5.4Hz),128.7,128.2,126.4(d,J＝8.7Hz),122.7,122.6,111.3(d,J＝20.0Hz),105.9,61.4,56.0,14.0。
19F NMR(376MHz,CDCl3)δ-119.9。
HRMS(APCI):calcd.for C23H19FNO3[M+H]+:376.13435,Found:376.13446。
example 171 Synthesis of ethoxycarbonyl-5, 7-dichloro-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝C6H5Para and ortho R to the amino group of the phenyl ring2═ Cl, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 77%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.32(d,J＝2.2Hz,1H),7.58–7.34(m,8H),3.61(d,J＝6.6Hz,2H),1.15(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.1,158.4(d,J＝263.1Hz),149.1,147.2(d,J＝2.7Hz),140.1(d,J＝12.6Hz),136.0,135.8,132.4,131.6,129.9(d,J＝5.9Hz),129.4,128.8,128.2(d,J＝8.3Hz),127.4,124.4,122.0,112.2(d,J＝19.5Hz),61.6,13.9。
19F NMR(376MHz,CDCl3)δ-119.6。
HRMS(APCI):calcd.for C22H15Cl2FNO2[M+H]+:414.04584,Found:414.04584。
example 181 Synthesis of ethyl ester-9-phenyl-4-fluoro [ c ] acridine
With chlorodifluoromethyl alkynimine (R)1＝C6H5Ortho-and meta-positions of the phenylamino group of the phenyl ring are acene, X ═ Cl) and ethyl alkenyldiazoacetate (R)3＝H，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 76%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ9.62(d,J＝7.4Hz,1H),7.91–7.76(m,3H),7.69–7.46(m,8H),3.61(q,J＝7.2Hz,2H),1.18(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.6,159.6(d,J＝261.8Hz),147.6,145.4,138.4(d,J＝11.8Hz),136.7,133.7,131.5,131.4,129.9,129.2,128.7(d,J＝5.5Hz),128.6,128.2,127.9,127.8,127.8,127.7,126.1,124.9,124.2,123.6,111.3(d,J＝19.9Hz),61.4,14.0。
19F NMR(376MHz,CDCl3)δ-118.9。
HRMS(APCI):calcd.for C26H19FNO2[M+H]+:396.13943,Found:396.14432。
example 191 Synthesis of n-butyl-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝Ph，R2H, X ═ Cl) and alkenyldiazon-butyl ester (R)3＝H，R4＝H，EWG＝COnBu) was used as a starting material, and a compound having the following structure was synthesized according to the method of example 1:
the yield was 76%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.64(d,J＝8.6Hz,1H),8.36(d,J＝8.7Hz,1H),7.92–7.85(m,1H),7.80–7.75(m,2H),7.74–7.68(m,2H),7.51–7.41(m,4H),4.26(t,J＝6.8Hz,2H),1.64–1.55(m,2H),1.32–1.20(m,2H),0.80(t,J＝7.4Hz,3H)。
13C NMR(100MHz,CDCl3)δ169.5,159.4(d,J＝262.5Hz),148.4 139.8(d,J＝12.9Hz),132.0,131.5,130.5,130.0,129.0(d,J＝5.6Hz),128.8,128.2,128.0,127.6(d,J＝8.6Hz),127.4(d,J＝3.7Hz),126.8,124.2,122.3,111.7(d,J＝20.1Hz),108.2,85.1,66.0,30.6,19.2,13.8。
19F NMR(376MHz,CDCl3)δ-118.6。
HRMS(APCI):calcd.for C24H21FNO2[M+H]+:374.15508,Found:374.15531。
EXAMPLE 201 Synthesis of allylester-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝Ph，R2H, X ═ Cl) and alkenyl diazoallyl esters (R)3＝H，R4＝H，EWG＝CO2C2H5) Starting from this, a compound having the following structure was synthesized according to the procedure of example 1:
the yield was 76%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.7Hz,1H),7.87–7.73(m,2H),7.63–7.38(m,8H),5.85–5.71(m,1H),5.27–5.15(m,2H),4.00(d,J＝5.8Hz,2H)。
13C NMR(100MHz,CDCl3)δ167.9,159.2(d,J＝262.5Hz),148.6,146.8(d,J＝2.8Hz),140.1(d,J＝12.4Hz),136.3,131.7,131.4,131.0,130.2,128.8,128.7(d,J＝5.7Hz),128.2,127.7(d,J＝8.8Hz),127.3,126.8,126.4,123.3,118.7,111.1(d,J＝20.1Hz),66.0。
19F NMR(376MHz,CDCl3)δ-118.6。
HRMS(APCI):calcd.for C23H17FNO2[M+H]+:358.12378,Found:358.12326。
example 211 Synthesis of ethoxycarbonyl-2-methyl-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝Ph，R2H, X ═ Cl) and ethyl α -methylenyldiazoacetate (R)3＝H，R4＝Me，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 76%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.37(d,J＝8.7Hz,1H),7.83–7.77(m,1H),7.75(d,J＝8.8Hz,1H),7.58–7.50(m,3H),7.49–7.41(m,4H),3.56(q,J＝7.2Hz,2H),2.55(d,J＝2.6Hz,3H),1.14(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.5,156.3(d,J＝258.2Hz),148.6,146.7,140.2(d,J＝12.6Hz),136.5,131.4(d,J＝6.0Hz),131.3,130.8,130.1,128.7,128.1,126.8,125.9,121.8,121.1(d,J＝16.6Hz),61.4,14.6(d,J＝3.4Hz),13.9。
19F NMR(376MHz,CDCl3)δ-124.6。
HRMS(APCI):calcd.for C23H19FNO2[M+H]+:360.13943,Found:360.13925。
example 221 Synthesis of carbethoxy-3-methyl-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝Ph，R2H, X ═ Cl) and ethyl β -methylenyldiazoacetate (R)3＝Me，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 67%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.34(d,J＝8.8Hz,1H),7.81–7.72(m,1H),7.57–7.49(m,3H),7.46–7.35(m,4H),7.31(d,J＝10.7Hz,1H),3.83(s,1H),3.23(s,1H),2.41(s,3H),1.16(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.7,157.9(d,J＝259.9Hz),147.8,145.9(d,J＝2.9Hz),138.8(d,J＝12.2Hz),135.5,134.3(d,J＝8.0Hz),131.7,130.5,130.0,128.8,127.6,127.2,127.0,127.0,126.9,122.9,115.2(d,J＝19.2Hz),61.2,20.4,13.8。
19F NMR(376MHz,CDCl3)δ-122.0。
HRMS(APCI):calcd.for C23H19FNO2[M+H]+:360.13943,Found:360.13965。
example 231 Synthesis of ethyl ester-3, 9-diphenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝Ph，R2H, X ═ Cl) and ethyl β -phenylalkenyldiazoacetate (R)3＝Ph，R4＝H，EWG＝CO2Et) as a starting material, a compound having the following structure was synthesized according to the method of example 1:
the yield was 33%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.7Hz,1H),7.82–7.67(m,5H),7.57–7.38(m,9H),3.53(q,J＝7.2Hz,2H),1.10(t,J＝7.2Hz,3H)。
13C NMR(100MHz,CDCl3)δ168.4,155.1(d,J＝263.3Hz),148.9,146.8,140.6(d,J＝12.8Hz),131.4,131.0,130.2,123.0,129.5(d,J＝3.5Hz),129.0,128.8,128.7,128.2,127.2,126.9,126.3,124.5(d,J＝13.0Hz),122.3,61.6,14.0。
19F NMR(376MHz,CDCl3)δ-125.0。
HRMS(APCI):calcd.forC28H21FNO2[M+H]+422.15508 and Found 422.15517. Example 241 Synthesis of p-toluoyl-9-phenyl-4-fluoroacridine
With chlorodifluoromethyl alkynimine (R)1＝Ph，R2H, X ═ Cl) and 1- (1-diazoenyl) -4-toluene (R)3＝H，R4H, EWG ═ p-MePhCO) as starting material, according to the method of example 1, compounds having the following structure were synthesized:
the yield was 29%.
Compound nuclear magnetic and high resolution data are as follows:
1H NMR(400MHz,CDCl3)δ8.41(d,J＝8.7Hz,1H),7.85–7.79(m,1H),7.60(d,J＝8.4Hz,1H),7.53–7.36(m,3H),7.31–7.17(m,5H),7.08–6.96(m,4H),2.36(s,3H)。
13C NMR(100MHz,CDCl3)δ195.2,158.9(d,J＝261.1Hz),148.6,147.5(d,J＝2.9Hz),144.0,140.2(d,J＝12.0Hz),135.8,135.7,134.9,131.8,131.1,130.1,129.7,128.7,128.6,127.8,127.1,127.0,127.0,126.95,126.6,125.0,111.3(d,J＝19.9Hz),21.8。
19F NMR(376MHz,CDCl3)δ-120.0。
HRMS(APCI):calcd.forC27H19FNO[M+H]+:392.14452,Found:392.14432。
it will be appreciated by those of ordinary skill in the art that the examples provided herein are intended to assist the reader in understanding the principles of the invention and are to be construed as being without limitation to such specifically recited examples and embodiments. Those skilled in the art can make various other specific changes and combinations based on the teachings of the present invention without departing from the spirit of the invention, and these changes and combinations are within the scope of the invention.
Claims (7)
1. A preparation method of a polysubstituted 4-fluoroacridine derivative is characterized by comprising the following steps: taking a photosensitizer as a catalyst, taking an organic solvent as a medium under the condition of visible light, carrying out free radical type domino cyclization reaction on a halogenated difluoromethyl alkyne imine compound shown in a formula (II) and an alkenyl diazo compound shown in a formula (III), and then removing hydrogen fluoride under the alkaline condition to obtain a 4-fluoroacridine derivative with the structure shown in the formula (I);
wherein R is1Is cycloalkyl, phenyl, alkylphenyl, alkoxyphenyl, halophenyl, nitrophenyl, polycyclic aryl, heterocyclyl;
R2～R4independently selected from hydrogen, alkyl, alkoxy, halogen or phenyl;
EWG is an ester group or an acyl group;
x is a halo group;
2. the method for preparing polysubstituted 4-fluoroacridine derivative according to claim 1, wherein said photosensitizer is one or more selected from the group consisting of ruthenium terpyridine chloride, ruthenium triphenanthroline chloride, iridium tris (2-phenylpyridine) complex, fluorescein, rose bengal, eosin Y and methyl blue.
3. The method for preparing polysubstituted 4-fluoroacridine derivative according to claim 1, wherein said photosensitizer is used in an amount of 1% by mole based on the amount of said halodifluoromethylenealkynimine compound.
4. The method for producing the polysubstituted 4-fluoroacridine derivative according to claim 1, wherein the molar ratio of the halogenated difluoromethyladenine compound to the ethylenic diazo compound is 1:1 to 1: 5.
5. The method for producing a polysubstituted 4-fluoroacridine derivative according to claim 1, wherein said radical-type domino cyclization is carried out under the following conditions: under the alkaline condition, the reaction time is 6-72 h, and the reaction temperature is 0-80 ℃.
6. The method for preparing a polysubstituted 4-fluoroacridine derivative according to claim 1, wherein said radical-type domino cyclization reaction further comprises the step of adding an electron donor compound to the reaction system; the electron donor compound is one or more of tri-n-butylamine, triethylamine, diisopropylethylamine or diethylamine.
7. The method for producing a polysubstituted 4-fluoroacridine derivative according to claim 1, wherein said basic condition is attained by adding an inorganic base or an organic base.
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