CN116589406A - Preparation method of polysubstituted acridine derivative - Google Patents

Preparation method of polysubstituted acridine derivative Download PDF

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Publication number
CN116589406A
CN116589406A CN202310357619.7A CN202310357619A CN116589406A CN 116589406 A CN116589406 A CN 116589406A CN 202310357619 A CN202310357619 A CN 202310357619A CN 116589406 A CN116589406 A CN 116589406A
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polysubstituted
reaction
compound
mmol
zinc
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欧阳紫君
庞鑫龙
朱硕
孙海燕
刘冬
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Shenzhen Polytechnic
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Shenzhen Polytechnic
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/02—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with only hydrogen, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C07D219/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The invention relates to the field of chemical synthesis, in particular to a preparation method of a polysubstituted acridine derivative. The main purpose of the invention is to produce an intermediate IV through the reaction of a compound II and a compound III in the presence of a palladium catalyst and a singlet oxygen catalyst; and the intermediate IV realizes electrophilic substitution reaction in the presence of Lewis acid and zinc catalyst to obtain the compound I. The method can provide a green and novel chemical synthesis method to obtain the acridine derivative, and can effectively improve the yield.

Description

Preparation method of polysubstituted acridine derivative
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of a polysubstituted acridine derivative.
Background
Acridine is an aromatic organic compound, has a molecular formula of C13H9N and is a light yellow needle-shaped solid, is a very important nitrogenous heterocyclic compound, and has been researched in a great deal in recent years, and acridine and various derivatives are gradually found to have unique physical, chemical properties and biological activities, so that the chemical industry (such as pigments, dyes and the like) of the compound, the fields of medicine (such as anti-tumor, antibacterial, antimalarial drugs, DNA and RNA intercalation and the like) and the like are widely applied. In addition, acridine derivatives containing large conjugated systems are promising as novel organic semiconductor materials because of their particular electronic and photophysical properties. The novel catalyst is prepared by forming a rigid structure through the dentate nitrogen atoms in the acridine derivative, and is also the direction of the catalysis workers.
The method for simply and efficiently synthesizing the acridine derivative is not reported so far, so that a brand new method for simply and high-yield preparation of the acridine derivative is necessary.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a polysubstituted acridine derivative, which can provide a green and novel chemical synthesis method for obtaining the acridine derivative and can effectively improve the yield.
The technical scheme adopted by the invention is as follows:
a preparation method of polysubstituted acridine derivatives, the structure of the polysubstituted acridine derivatives is shown as formula (I),
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Independently selected from hydrogen, halogen, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 6～20 Aryl, substituted or unsubstituted C 1～10 Alkoxy, carboxyl, C 2～10 Ester group of (C), substituted or unsubstitutedAny one of amino, acyl, cyano, nitro, hydroxy or azido;
the preparation method of the polysubstituted acridine derivative, namely the compound I, has the following formula:
the preparation method comprises the following steps:
the compound II and the compound III react in the presence of a palladium catalyst and a singlet oxygen catalyst to generate an intermediate IV;
and the intermediate IV realizes electrophilic substitution reaction in the presence of Lewis acid and zinc catalyst to obtain the compound I.
The preparation method also comprises the step of adding a bidentate ligand coordinated with the palladium catalyst.
The palladium catalyst is one or a combination of more of palladium acetate, palladium chloride, tetraphenylphosphine palladium or di (tri-tert-butylphosphine) palladium.
The singlet oxygen catalyst is a conjugated polymer PFOTTzT.
The Lewis acid is one or a combination of more of zinc chloride, copper triflate, zinc triflate, nickel chloride, p-toluenesulfonic acid and trifluoromethanesulfonic acid.
The zinc catalyst is one or a combination of more of zinc chloride, zinc bromide, zinc iodide, zinc phosphate, zinc acetate, zinc sulfate or zinc carbonate.
The mol ratio of the compound II to the compound III is 1:1-1.5
The preparation method further comprises the following steps: the reaction temperature is 40-150 ℃.
The preparation method further comprises the following steps: the reaction time is 1-24 h.
Purifying the obtained compound I after the electrophilic substitution reaction is finished, wherein the purification adopts concentration or column chromatography purification; concentrating, and evaporating the solvent by normal pressure distillation, reduced pressure distillation or rotary evaporation; column chromatography uses 200-300 mesh silica gel as separating resin.
The beneficial effects of the invention are as follows: (1) The preparation method is environment-friendly, the singlet oxygen photosensitizer required by the reaction can be recycled, air is used as an oxidant, the environment is not polluted, the light source is sunlight, the operation is simple and safe, the reaction steps are few, the raw materials are easy to obtain, the reaction condition is mild, no byproducts are generated, the substrate expansion range is wide, the tolerance of the compound functional group is high, and the product yield can reach more than 82%;
(2) The reaction method is a method for obtaining the acridine derivative by one-step serial cyclization reaction, and step-by-step reaction is not needed. The operating time and steps of the operator can be saved, and thus, the reduction of the labor cost, which is a cost of the maximum specific gravity in the organic synthesis, can be achieved, as is well known. The synthesis cost is reduced, so that the synthesis cost of the target compound can be greatly improved;
(3) The reaction method is more in line with the concept of atom economy, and the method is characterized in that when the conjugated polymer is subjected to illumination (sunlight), the conjugated polymer and oxygen molecules in the air are subjected to energy transfer, so that singlet oxygen is generated. Oxidative coupling reaction between C-H and N-H using singlet oxygen as an oxidant, which loses only one molecule of H 2 Under the oxidation of singlet oxygen, a molecule H is generated 2 O, no pollution to environment. And no additional addition of base is required. Therefore, the method accords with the ideas of atom economy and green synthesis.
Drawings
FIG. 1 shows the compound (I-a) prepared in example 1 1 H NMR chart;
FIG. 2 shows the compound (I-a) prepared in example 1 13 C NMR chart;
FIG. 3 shows the compound (I-b) prepared in example 1 1 H NMR chart;
FIG. 4 shows the compound (I-b) prepared in example 1 13 C NMR chart;
FIG. 5 shows the compound (I-c) prepared in example 1 1 H NMR chart;
FIG. 6 shows the compound (I-c) prepared in example 1 13 C NMR chart;
FIG. 7 shows the compound (I-d) prepared in example 1 1 H NMR chart；
FIG. 8 shows the compound (I-d) prepared in example 1 13 C NMR chart;
FIG. 9 shows the compound (I-e) prepared in example 1 1 H NMR chart;
FIG. 10 shows the compound (I-e) prepared in example 1 13 C NMR chart;
FIG. 11 shows the compound (I-f) prepared in example 1 1 H NMR chart;
FIG. 12 shows the compound (I-f) prepared in example 1 13 C NMR chart;
FIG. 13 shows the compound (I-g) prepared in example 1 1 H NMR chart;
FIG. 14 shows the compound (I-g) prepared in example 1 13 C NMR chart;
FIG. 15 shows the compound (I-h) prepared in example 1 1 H NMR chart;
FIG. 16 shows the compound (I-h) prepared in example 1 13 C NMR chart;
FIG. 17 shows the compound (I-i) prepared in example 1 1 H NMR chart;
FIG. 18 shows the compound (I-i) prepared in example 1 13 C NMR chart;
FIG. 19 shows the compound (I-j) prepared in example 1 1 H NMR chart;
FIG. 20 shows the compound (I-j) prepared in example 1 13 C NMR chart;
FIG. 21 shows the compound (I-k) prepared in example 1 1 H NMR chart;
FIG. 22 shows the compound (I-k) prepared in example 1 13 C NMR chart;
FIG. 23 shows the compound (I-l) prepared in example 1 1 H NMR chart;
FIG. 24 shows the compound (I-l) prepared in example 1 13 C NMR chart;
Detailed Description
Example 1
Example 1 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magneton was added, 3mL dioxane was screwed up, the tube seal was transferred into an oil bath at 70℃and stirred, and a 120W white light reaction was given sideways overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-a) was obtained as pure product in the form of a yellow solid with a separation yield of 95%.
The second method is as follows: acetophenone (1 mmol,120 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magneton, 3mL dioxane was added, the tube sealer was screwed down, and it was transferred into an oil bath at 70℃and stirred, and a 120W white light was laterally applied to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- (phenylamino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-a) was obtained as pure product in a yellow solid, isolated in a yield of 87%.
Structural identification of structural formula (I-a):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ8.37–8.12(m,4H),7.76(ddd,J＝6.5,3.8,0.7Hz,2H),7.63–7.45(m,2H),3.11(s,3H) 13 C NMR(76MHz,CHLOROFORM-D)δ148.6(2×C),142.3(2×C),130.4(2×CH),129.8(2×CH),125.6(2×C),125.5(2×C),124.6(2×CH),13.7(2×CH).
mp:117-118℃；
ESI-HRMS:m/z calcd for C 14 H 11 N[M+H] + :194.0891；found:194.0893；GC-MS:193.
the compounds of formula (I-a) 1 H NMR 13 The C NMR spectra are shown in FIG. 1 and FIG. 2, and the analysis result shows that the obtained target product is correct.
Example 2
Example 2 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), toluidine (107 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magnet was added, 3mL dioxane was screwed up, the tube seal was transferred into an oil bath at 70℃and stirred, and 120W white light was laterally applied overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-b) was obtained as pure product in a yellow solid with a separation yield of 94%.
The second method is as follows: acetophenone (1 mmol,120 mg), para-toluidine (107 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magnet was added, 3mL dioxane was screwed down, the tube sealer was transferred into an oil bath at 130℃and stirred, and a 120W white light was applied sideways to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- (p-toluylamino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-b) was obtained as pure product in a yellow solid with a separation yield of 82%.
Structural identification of the compound of (I-b):
nuclear magnetic resonance data:
1 H NMR(400MHz,CHLOROFORM-D)δ8.18(d,J＝8.5Hz,2H),8.10(d,J＝8.8Hz,1H),7.93(s,1H),7.70(dd,J＝8.3,6.9Hz,1H),7.57(d,J＝8.9Hz,1H),7.53–7.46(m,1H),6.43(d,J＝1.5Hz,1H),3.04(s,3H),2.57(s,3H)； 13 C NMR(76MHz,CHLOROFORM-D)δ148.1,147.5,141.0,135.2,132.7,130.3,130.0,129.3,125.8,125.6,125.4,124.5,122.9,22.3,13.6.
ESI-HRMS:m/z calcd for C15H13N[M+H]+:208.1048；found:208.1046；GC-MS:207.
(I-b) Compounds 1 H NMR 13 The C NMR spectra are shown in FIG. 3 and FIG. 4: analysis results show that the obtained target product is correct.
Example 3
Example 3 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), o-toluidine (107 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magneton was added, 3mL dioxane was screwed up, the tube seal was transferred into an oil bath at 130℃and stirred, and a 120W white light was laterally applied overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-c) was obtained as pure product in a yellow solid, isolated in 96% yield.
The second method is as follows: acetophenone (1 mmol,120 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magnet, 3mL dioxane was added, the tube sealer was screwed, and it was transferred into an oil bath at 130℃and stirred, and a 120W white light was laterally applied to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- (phenylamino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-c) was obtained as pure product in a yellow solid, isolated in 86% yield.
Structural identification of compounds of formula (I-c):
nuclear magnetic resonance data:
1 H NMR(400MHz,CHLOROFORM-D)δ8.26(d,J＝8.7Hz,1H),8.20(d,J＝8.8Hz,1H),8.07(d,J＝9.3Hz,1H),7.73(ddd,J＝8.6,6.5,1.3Hz,1H),7.62–7.57(m,1H),7.52(ddd,J＝8.6,6.5,1.2Hz,1H),7.42(dd,J＝8.8,6.7Hz,1H),3.07(s,3H),2.95(s,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ148.1,147.8,141.8,138.0,131.0,129.2,129.1,125.5,125.4(2×CH),125.2,124.4,122.6,18.9,13.8.
ESI-HRMS:m/z calcd for C15H13N[M+H]+:208.1048；found:208.1046；GC-MS:207.
the compounds of the formula (I-c) 1 H NMR 13 The C NMR spectra are shown in FIGS. 5 and 6: analysis results show that the obtained target product is correct.
Example 4
Example 4 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), o-methoxyaniline (123 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magneton was added, 3mL dioxane was screwed up, the tube seal was transferred into an oil bath at 70℃and stirred, and a 120W white light reaction was given sideways overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-d) was obtained as pure product in the form of a yellow solid with a separation yield of 93%.
The second method is as follows: acetophenone (1 mmol,120 mg), o-methoxyaniline (123 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube seal, the magnet was added, 3mL dioxane was screwed down, the tube seal was transferred into an oil bath at 130℃and stirred, and a 120W white light was applied sideways to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- ((2-methoxyphenyl) amino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-d) was obtained as pure product in a yellow solid with a separation yield of 80%.
Structural identification of the compound of formula (I-d):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ8.37(d,J＝8.7Hz,1H),8.19(d,J＝8.7Hz,1H),7.77(dd,J＝9.0,0.8Hz,1H),7.74–7.68(m,1H),7.61–7.48(m,1H),7.42(dd,J＝8.8,7.6Hz,1H),7.00(d,J＝7.4Hz,1H),4.13(s,3H),3.05(s,3H)； 13 C NMR(76MHz,CHLOROFORM-D)δ155.6,147.5,142.1,141.7,131.2,129.4,126.6,125.9,125.9,125.3,124.3,116.5,106.1,56.3,14.1.
ESI-HRMS:m/z calcd for C15H13NO[M+H]+:224.0997；found:224.0989；GC-MS:223.
the compounds of the formula (I-d) 1 H NMR 13 C NMR spectra as shown in fig. 7 and 8: analysis results show that the obtained target product is correct.
Example 5
Example 5 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), para-fluoroaniline (111 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magneton, 3mL dioxane was added, the tube seal was screwed down, transferred into an oil bath at 70℃and stirred, and a 120W white light reaction was given sideways overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-e) was obtained as pure product in the form of a yellow solid with a separation yield of 92%.
The second method is as follows: acetophenone (1 mmol,120 mg), para-fluoroaniline (111 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube seal, the magnet, 3mL dioxane were added, the tube seal was tightened, and it was transferred into an oil bath at 130℃and stirred, and a 120W white light was applied sideways to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- ((4-fluorophenyl) amino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-e) was obtained as pure product in the form of a yellow solid with a separation yield of 78%.
Structural identification of compounds of formula (I-e):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ8.01(d,J＝8.8Hz,1H),7.65(dd,J＝8.8,1.6Hz,1H),7.54(s,1H),7.48-7.36(m,3H),7.15-7.08(m,2H),3.11(t,J＝6.5Hz,2H),2.51(t,J＝6.4Hz,2H),1.92-1.82(m,2H),1.74-1.63(m,2H). 13 C NMR(76MHz,CHLOROFORM-D)δ161.76,147.43,147.32,136.07,130.03,129.70,129.05(2×CH),128.96(2×CH),128.35,127.26(q,J＝32.3Hz),125.84,124.27(q,J＝272.4Hz),124.08(q,J＝2.8Hz),123.84(q,J＝4.4Hz),34.48,28.18,22.89,22.77.
ESI-HRMS:m/z calcd for C 20 H 16 F 3 N[M+H] + :328.1308；found:328.1309.
1 H NMR(400MHz,CHLOROFORM-D)δ8.29–8.06(m,3H),7.74(ddd,J＝12.3,8.2,1.9Hz,2H),7.60–7.49(m,2H),3.00(s,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ159.8(d,J＝248.4Hz),148.0,145.9,141.4,133.1(d,J＝9.0Hz),130.4,129.7,126.1,125.8(d,J＝9.0Hz),125.6,124.3,121.4(d,J＝27.9Hz),106.8(d,J＝22.4Hz),13.9.
ESI-HRMS:m/z calcd for C14H10FN[M+H]+:212.0797；found:212.0791；GC-MS:211.
compounds of formula (I-e) 1 H NMR 13 The C NMR spectra are shown in FIG. 9 and FIG. 10, and the analysis result shows that the obtained target product is correct.
Example 6
Example 6 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: propiophenone (1 mmol,120 mg), para-toluidine (107 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magnet was added, 3mL dioxane was screwed up, the tube seal was transferred into an oil bath at 70℃and stirred, and a 120W white light was laterally applied overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-f) was obtained as pure product in the form of a yellow solid with a separation yield of 95%.
The second method is as follows: propiophenone (1 mmol,120 mg), para-toluidine (107 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magnet was added, 3mL dioxane was screwed down, the tube sealer was transferred into an oil bath at 130℃and stirred, and 120W white light was laterally applied for reaction overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- (p-toluylamino) phenyl) propan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-f) was obtained as pure product in a yellow solid, isolated in 79% yield.
Structural identification of compounds of formula (I-f):
nuclear magnetic resonance data:
1 H NMR(400MHz,CHLOROFORM-D)δ8.18(d,J＝8.7Hz,1H),8.09(dd,J＝8.8,2.5Hz,2H),7.84(s,1H),7.66(dd,J＝8.0,7.2Hz,1H),7.51(d,J＝8.8Hz,1H),7.43(dd,J＝8.0,7.3Hz,1H),3.45(q,J＝7.6Hz,2H),2.50(s,3H),1.35(t,J＝7.6Hz,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ148.19,147.64,147.17,135.30,132.70,130.36,130.08,129.35,125.50,124.66,124.54,124.18,122.40,22.35,20.76,15.48.
ESI-HRMS:m/z calcd for C14H11N[M+H]+:208.1048；found:208.1053；GC-MS:207.
the compounds of formula (I-f) 1 H NMR 13 The C NMR spectra are shown in FIG. 11 and FIG. 12, and the analysis result shows that the obtained target product is correct.
Example 7
Example 7 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), o-chloroaniline (127 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magneton, 3mL dioxane was added, the tube seal was screwed down, transferred into an oil bath at 70℃and stirred, and a 120W white light reaction was given sideways overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-g) was obtained as pure product in a yellow solid with a separation yield of 97%.
The second method is as follows: acetophenone (1 mmol,120 mg), o-chloroaniline (127 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube seal, the magnet, 3mL dioxane were added, the tube seal was tightened, and it was transferred into an oil bath at 130℃and stirred, and a 120W white light was applied sideways to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- ((2-chlorophenyl) amino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-g) was obtained as pure product in the form of a yellow solid with a separation yield of 83%.
Structural identification of the compound of formula (I-g):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ7.88(dd,J＝9.2,5.5Hz,1H),7.37(tdd,J＝6.8,4.5,2.2Hz,3H),7.27-7.18(m,1H),7.12-7.06(m,2H),6.81(dd,J＝10.2,2.8Hz,1H),3.06(t,J＝6.5Hz,2H),2.48(t,J＝6.4Hz,2H),1.89-1.78(m,2H),1.71-1.59(m,2H).13C NMR(76MHz,CHLOROFORM-D)δ159.99(d,J＝245.5Hz),158.47(d,J＝2.3Hz),146.05(d,J＝5.5Hz),143.54,136.73,130.88(d,J＝9.1Hz),129.27129.05(2×CH),128.87(2×CH),128.06,127.44(d,J＝9.3Hz),118.52(d,J＝25.8Hz),109.06(d,J＝22.8Hz),34.20,28.20,23.02,22.96；
ESI-HRMS:m/z calcd for C 19 H 16 FN[M+H] + :278.1340；found:278.1337.
1 H NMR(400MHz,CHLOROFORM-D)δ8.33–8.26(m,1H),8.09(ddd,J＝28.0,8.3,0.9Hz,2H),7.83(d,J＝7.2Hz,1H),7.79–7.70(m,1H),7.56–7.47(m,1H),7.34(t,J＝8.0Hz,1H),3.00(s,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ148.5,144.5,143.2,134.0,131.0,130.2,129.4,126.4,126.2,125.7,124.7,124.4,123.9,14.1.
ESI-HRMS:m/z calcd for C14H10ClN[M+H]+:228.0502；found:228.0511；GC-MS:227.
the compounds of the formula (I-g) 1 H NMR 13 The C NMR spectra are shown in FIG. 13 and FIG. 14, and the analysis result shows that the obtained target product is correct.
Example 8
Example 8 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), 2, 4-dimethylaniline (121 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magnet, 3mL dioxane was added, the tube seal was tightened, transferred into an oil bath at 70℃and stirred, and the side was left to react overnight with 120W white light. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-h) was obtained as pure product in a yellow solid with a separation yield of 97%.
The second method is as follows: acetophenone (1 mmol,120 mg), 2, 4-dimethylaniline (121 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magnet was added, 3mL dioxane was screwed down the tube sealer, and the tube sealer was transferred into an oil bath at 130℃and stirred, and side was allowed to react overnight with 120W white light. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- ((2, 4-dimethylphenyl) amino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-h) was obtained as pure product in a yellow solid, isolated in 79% yield.
Structural identification of compounds of formula (I-h):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ7.83(d,J＝8.9Hz,1H),7.45-7.30(m,4H),7.17(d,J＝2.3Hz,1H),7.09(dd,J＝7.7,1.4Hz,2H),3.06(t,J＝6.5Hz,2H),2.47(t,J＝6.4Hz,2H),1.90-1.76(m,2H),1.73-1.56(m,2H)； 13 C NMR(76MHz,CHLOROFORM-D)δ159.55,145.76,144.78,136.46,131.22,130.19,129.50,129.29,129.09(2×CH),128.90(2×CH),128.13,127.46,124.61,34.30,28.20,22.99,22.89；
ESI-HRMS:m/z calcd for C 19 H 16 ClN[M+H] + :293.7940；found 293.7838.
1 H NMR(301MHz,CHLOROFORM-D)δ8.25(d,J＝8.7Hz,1H),8.16(d,J＝8.8Hz,1H),7.77(s,1H),7.74–7.67(m,1H),7.50(ddd,J＝8.6,6.6,1.2Hz,1H),7.43(s,1H),3.00(s,3H),2.92(s,3H),2.54(s,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ147.2,146.9,140.5,137.4,134.7,132.1,130.9,128.8,125.5,125.5,125.2,124.4,120.8,22.4,18.7,13.7.
ESI-HRMS:m/z calcd for C16H15N[M+H]+:222.1204；found:222.1208；GC-MS:221.
compounds of formula (I-h) 1 H NMR 13 The C NMR spectra are shown in FIG. 15 and FIG. 16, and the analysis result shows that the obtained target product is correct.
Example 9
Example 9 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: acetophenone (1 mmol,120 mg), 1-naphthylamine (143 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, the magneton, 3mL dioxane was added, the tube seal was screwed, transferred into an oil bath at 70℃and stirred, and a 120W white light was laterally applied overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-I) was obtained as pure product in a yellow solid with a separation yield of 98%.
The second method is as follows: acetophenone (1 mmol,120 mg), 1-naphthylamine (143 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magnet was added, 3mL dioxane was screwed up, the tube sealer was transferred into an oil bath at 130℃and stirred, and 120W white light was laterally applied for reaction overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (2- (naphthalen-1-ylamino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-I) was obtained as pure product in a yellow solid, isolated in 89% yield.
Structural identification of compounds of formula (I-I):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ7.83(d,J＝8.9Hz,1H),7.45-7.30(m,4H),7.17(d,J＝2.3Hz,1H),7.09(dd,J＝7.7,1.4Hz,2H),3.06(t,J＝6.5Hz,2H),2.47(t,J＝6.4Hz,2H),1.90-1.76(m,2H),1.73-1.56(m,2H)； 13 C NMR(76MHz,CHLOROFORM-D)δ159.55,145.76,144.78,136.46,131.22,130.19,129.50,129.29,129.09(2×CH),128.90(2×CH),128.13,127.46,124.61,34.30,28.20,22.99,22.89；
ESI-HRMS:m/z calcd for C 19 H 16 ClN[M+H] + :293.7940；found 293.7838.
1 H NMR(301MHz,CHLOROFORM-D)δ9.56(dd,J＝7.8,0.9Hz,1H),8.46–8.25(m,1H),8.24–8.09(m,1H),7.89(d,J＝9.4Hz,1H),7.85–7.69(m,4H),7.64–7.58(m,1H),7.58–7.53(m,1H),2.96(s,3H)； 13 C NMR(76MHz,CHLOROFORM-D)δ147.1,147.1,140.9,133.6,132.2,130.7,129.2,128.9,127.7,127.3,127.1,126.3,125.7(2×CH),124.3,123.5,122.2,13.7.
ESI-HRMS:m/z calcd for C18H13N[M+H]+:244.1048；found:244.1051；GC-MS:243.
the compounds of formula (I-I) 1 H NMR 13 The C NMR spectra are shown in FIG. 17 and FIG. 18, and the analysis resultsIndicating that the target product obtained was correct.
Example 10
Example 10 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: 1- (3-bromophenyl) ethan-1-one (1 mmol, 199mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, a magnet, 3mL dioxane was added, the tube seal was tightened, and moved into an oil bath at 70℃and stirred, and a 120W white light was applied sideways to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-j) was obtained as pure product in the form of a yellow solid with a separation yield of 93%.
The second method is as follows: 1- (3-bromophenyl) ethan-1-one (1 mmol, 199mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube sealer, the magneton was added, 3mL dioxane was screwed down, the tube sealer was transferred into an oil bath at 130℃and stirred, and a 120W white light reaction was given sideways overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (5-bromo-2- (phenylamino) phenyl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-j) was obtained as pure product in a yellow solid, isolated in 89% yield.
Structural identification of compounds of formula (I-j):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ7.83(d,J＝8.9Hz,1H),7.45-7.30(m,4H),7.17(d,J＝2.3Hz,1H),7.09(dd,J＝7.7,1.4Hz,2H),3.06(t,J＝6.5Hz,2H),2.47(t,J＝6.4Hz,2H),1.90-1.76(m,2H),1.73-1.56(m,2H)； 13 C NMR(76MHz,CHLOROFORM-D)δ159.55,145.76,144.78,136.46,131.22,130.19,129.50,129.29,129.09(2×CH),128.90(2×CH),128.13,127.46,124.61,34.30,28.20,22.99,22.89；
ESI-HRMS:m/z calcd for C 19 H 16 ClN[M+H] + :293.7940；found 293.7838.
1 H NMR(400MHz,CHLOROFORM-D)δ8.38(d,J＝2.0Hz,1H),8.19(dd,J＝15.6,8.7Hz,2H),8.06(d,J＝9.2Hz,1H),7.81–7.74(m,2H),7.58–7.53(m,1H),3.04(s,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ148.7,146.8,141.5,133.3,132.1,130.4,130.2,126.8,126.5,126.2,125.8,124.6,119.8,13.8.
ESI-HRMS:m/z calcd for C14H10BrN[M+H]+:271.9997；found:271.9989；GC-MS:270.
compounds of formula (I-j) 1 H NMR 13 The C NMR spectra are shown in FIG. 19 and FIG. 20, and the analysis result shows that the obtained target product is correct.
Example 11
Example 11 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: 1- (1, 1' -Biphenyl) -3-yl) ethan-1-one (1 mmol,196 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg), zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, magneton was added, 3mL dioxane was added, the tube seal was tightened, and it was transferred into an oil bath at 70℃and stirred, and a 120W white light reaction was given sideways overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-k) was obtained as pure product in the form of a yellow solid with a separation yield of 95%.
The second method is as follows: 1- (1, 1' -Biphenyl) -3-yl) ethan-1-one (1 mmol,196 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube seal, the magnet, 3mL dioxane, the tube seal was tightened, transferred into a 130℃oil bath and stirred, and the side was left to react overnight with 120W white light. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (4- (phenylamino) - [1,1' -biphenyl ] -3-yl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-k) was obtained as pure product in the form of a yellow solid with a separation yield of 91%.
Structural identification of the compound of formula (I-k):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ7.83(d,J＝8.9Hz,1H),7.45-7.30(m,4H),7.17(d,J＝2.3Hz,1H),7.09(dd,J＝7.7,1.4Hz,2H),3.06(t,J＝6.5Hz,2H),2.47(t,J＝6.4Hz,2H),1.90-1.76(m,2H),1.73-1.56(m,2H)； 13 C NMR(76MHz,CHLOROFORM-D)δ159.55,145.76,144.78,136.46,131.22,130.19,129.50,129.29,129.09(2×CH),128.90(2×CH),128.13,127.46,124.61,34.30,28.20,22.99,22.89；
ESI-HRMS:m/z calcd for C 19 H 16 ClN[M+H] + :293.7940；found 293.7838.
1 H NMR(301MHz,CHLOROFORM-D)δ8.40(d,J＝1.8Hz,1H),8.26(dd,J＝18.9,8.6Hz,3H),8.05(dd,J＝9.0,1.8Hz,1H),7.79(d,J＝7.5Hz,3H),7.55(dd,J＝15.6,8.1Hz,3H),7.44(d,J＝7.2Hz,1H),3.16(s,3H)； 13 C NMR(76MHz,CHLOROFORM-D)δ148.6,148.0,142.4,140.9,138.1,130.9,130.4,130.1,129.8,129.1(2×CH),127.8,127.6(2×CH),125.9,125.7,125.7,124.6,122.2,13.8.
ESI-HRMS:m/z calcd for C20H15N[M+H]+:270.1204；found:270.1207；GC-MS:269.
the compounds of formula (I-k) 1 H NMR 13 The C NMR spectra are shown in FIG. 21 and FIG. 22, and the analysis result shows that the obtained target product is correct.
Example 12
Example 12 provides a method for preparing polysubstituted acridine derivatives, which has the following structural formula and preparation method:
the method comprises the following steps: 1- (benzo [ d ] [1,3] dioxol-5-yl) ethan-1-one (1 mmol, 64 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) and zinc chloride (0.1 mmol,14 mg) were weighed into a 25mL tube seal, a magnet was added, 3mL dioxane was screwed into the tube seal, and the tube seal was moved into an oil bath at 70℃and stirred, and a 120W white light was laterally supplied for reaction overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-l) was obtained as pure product in a yellow solid, isolated in 96% yield.
The second method is as follows: 1- (benzo [ d ] [1,3] dioxol-5-yl) ethan-1-one (1 mmol,164 mg), aniline (93 mg), palladium acetate (0.1 mmol,17 mg), PFOTTzT (0.02 mmol,14 mg) were weighed into a 25mL tube seal, magneton, 3mL dioxane was added, the tube seal was screwed, and transferred into an oil bath at 130℃and stirred, and a 120W white light was laterally applied to react overnight. The reaction was followed by TLC, and after the completion of the reaction, the tube was sealed and cooled to room temperature. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=8:1, pure 1- (6- (phenylamino) benzo [ d ] [1,3] dioxo-5-yl) ethan-1-one was obtained.
Zinc chloride (0.1 mmol,14 mg) and all reaction products of the above steps are weighed into a 25mL sealed tube, magnetons are added, the sealed tube is replaced by high-purity nitrogen for three times, 3mL of dichloroethane is added into the sealed tube under the protection of the nitrogen, the sealed tube is screwed up, and the reaction is carried out under stirring at normal temperature. The reaction was followed by TLC detection and after completion. Adding 5mL of distilled water into the system, and stirring; extraction with diethyl ether (5 mL. Times.3). Combining the organic phases, and removing the solvent by using a rotary evaporator to obtain a crude product; the crude product is carried by silica gel, and the eluent adopts petroleum ether with the volume ratio: after column chromatography purification of ethyl acetate=7:1, the compound of formula (I-l) was obtained as pure product in the form of a yellow solid in an isolated yield of 87%.
Structural identification of the compound of formula (I-l):
nuclear magnetic resonance data:
1 H NMR(301MHz,CHLOROFORM-D)δ7.83(d,J＝8.9Hz,1H),7.45-7.30(m,4H),7.17(d,J＝2.3Hz,1H),7.09(dd,J＝7.7,1.4Hz,2H),3.06(t,J＝6.5Hz,2H),2.47(t,J＝6.4Hz,2H),1.90-1.76(m,2H),1.73-1.56(m,2H)； 13 C NMR(76MHz,CHLOROFORM-D)δ159.55,145.76,144.78,136.46,131.22,130.19,129.50,129.29,129.09(2×CH),128.90(2×CH),128.13,127.46,124.61,34.30,28.20,22.99,22.89；
ESI-HRMS:m/z calcd for C 19 H 16 ClN[M+H] + :293.7940；found 293.7838.
1 H NMR(400MHz,CHLOROFORM-D)δ8.08(d,J＝8.7Hz,2H),7.69–7.62(m,1H),7.45(ddd,J＝8.4,6.6,1.2Hz,1H),7.36(s,1H),7.30(s,1H),6.07(s,2H),2.88(s,3H)； 13 C NMR(101MHz,CHLOROFORM-D)δ151.56,147.94,147.74,147.07,139.65,129.58,128.79,124.89,124.82,124.10,123.11,104.70,101.82,98.54,14.02.
ESI-HRMS:m/z calcd for C15H11NO2[M+H]+:238.0790；found:238.0783；GC-MS:237.
the compounds of formula (I-l) 1 H NMR 13 The C NMR spectra are shown in FIG. 23 and FIG. 24, and the analysis result shows that the obtained target product is correct.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.

Claims (10)

1. A preparation method of polysubstituted acridine derivatives, the structure of the polysubstituted acridine derivatives is shown as formula (I),
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Independently selected from hydrogen, halogen, substituted or unsubstituted C 1～10 Alkyl, substituted or unsubstituted C 6～20 Aryl, substituted or unsubstituted C 1～10 Alkoxy, carboxyl, C 2～10 Any one of an ester group, a substituted or unsubstituted amino group, an acyl group, a cyano group, a nitro group, a hydroxyl group, or an azide group;
the preparation method of the polysubstituted acridine derivative is characterized in that the preparation method of the compound I is as follows:
the preparation method comprises the following steps:
the compound II and the compound III react in the presence of a palladium catalyst and a singlet oxygen catalyst to generate an intermediate IV;
and the intermediate IV realizes electrophilic substitution reaction in the presence of Lewis acid and zinc catalyst to obtain the compound I.
2. The method for preparing the polysubstituted acridine derivative according to claim 1, wherein the method is characterized in that: the preparation method also comprises the step of adding a bidentate ligand coordinated with the palladium catalyst.
3. The method for preparing the polysubstituted acridine derivative according to claim 2, wherein the method is characterized in that: the palladium catalyst is one or a combination of more of palladium acetate, palladium chloride, tetraphenylphosphine palladium or di (tri-tert-butylphosphine) palladium.
4. The method for preparing the polysubstituted acridine derivative according to claim 1, wherein the method is characterized in that: the singlet oxygen catalyst is a conjugated polymer PFOTTzT.
5. The method for preparing the polysubstituted acridine derivative according to claim 1, wherein the method is characterized in that: the Lewis acid is one or a combination of more of zinc chloride, copper triflate, zinc triflate, nickel chloride, p-toluenesulfonic acid and trifluoromethanesulfonic acid.
6. The method for preparing the polysubstituted acridine derivative according to claim 1, wherein the method is characterized in that: the zinc catalyst is one or a combination of more of zinc chloride, zinc bromide, zinc iodide, zinc phosphate, zinc acetate, zinc sulfate or zinc carbonate.
7. The process for producing a polysubstituted acridine derivative according to any one of claims 1 to 6, wherein: the mol ratio of the compound II to the compound III is 1:1-1.5.
8. The process for producing a polysubstituted acridine derivative according to any one of claims 1 to 7, wherein: the preparation method further comprises the following steps: the reaction temperature is 40-150 ℃.
9. The process for producing a polysubstituted acridine derivative according to any one of claims 1 to 7, wherein: the preparation method further comprises the following steps: the reaction time is 1-24 h.
10. The process for producing a polysubstituted acridine derivative according to any one of claims 1 to 7, wherein: purifying the obtained compound I after the electrophilic substitution reaction is finished, wherein the purification adopts concentration or column chromatography purification; concentrating, and evaporating the solvent by normal pressure distillation, reduced pressure distillation or rotary evaporation; column chromatography uses 200-300 mesh silica gel as separating resin.
CN202310357619.7A 2023-04-06 2023-04-06 Preparation method of polysubstituted acridine derivative Pending CN116589406A (en)

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