CN106631820A - Method for preparing aromatic amine compounds - Google Patents

Method for preparing aromatic amine compounds Download PDF

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CN106631820A
CN106631820A CN201611194847.3A CN201611194847A CN106631820A CN 106631820 A CN106631820 A CN 106631820A CN 201611194847 A CN201611194847 A CN 201611194847A CN 106631820 A CN106631820 A CN 106631820A
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aromatic amine
amine compounds
alkyl
dichloromethane
compounds according
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柳文媛
曲玮
蒋学阳
冯锋
郝艳峰
周越
李凌超
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
    • C07C209/18—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/14—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/20—Hydroxylamino compounds or their ethers or esters having oxygen atoms of hydroxylamino groups etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C241/02—Preparation of hydrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a method for preparing aromatic amine compounds. The method comprises the following steps: mixing and dissolving a phenol compound and amine in a solvent according to a molar ratio of 1:(2-40) under protection of inert gas, performing reaction for 6 to 15 hours at 50 to 140 DEG C to prepare corresponding aromatic amine compounds, and performing posttreatment to obtain pure aromatic amine compounds. According to the method, the raw materials are common and highly available, the method is easy to operate and applicable to industrial production, a substrate is wide in application range, and nucleophilic addition reaction can be performed on the phenol compound to obtain the corresponding aromatic amine compounds in the absence of a catalyst; existence of water in a reaction system is allowed, and first-level aromatic amine compounds can be successfully prepared from phenolic hydroxy by adopting ammonia water or hydrazine hydrate as the substrate and adopting ammonium chloride as a catalyst and a co-solvent; selectivity to the phenolic hydroxy is relatively high, and influence on reaction can be prevented even though a halogen atom exists in the substrate.

Description

A kind of method for preparing aromatic amine compounds
Technical field
The invention belongs to the preparation field of aromatic amine compounds, and in particular to a kind of side for preparing aromatic amine compounds Method, it is particularly a kind of by phenolic compound without under catalysts conditions generate aromatic amine method.
Background technology
It is important in medicine and chemical field during aromatic amine compound (Arylamines) is widely present in natural products Raw material and intermediate, are wide variety of chemical raw materials in the chemical industries such as macromolecular material, agricultural and dyestuff.Aromatic amine chemical combination Thing synthesis majority is realized by the structure of C-N keys.At present the method for synthesis aromatic amine has a lot, mainly there is Ullmann and Goldberg and Buchwald-Hartwig reacts, Michael-addition reactions, Mannich reactions, Baylis- Hillman reactions etc..With industry and economic development with rapid changepl. never-ending changes and improvements, each relevant industries are more next to the demand of aromatic amine compound It is bigger, thus develop aromatic amine compound synthesis neomethodology research have great importance.
Substituted aroma amines plays the role of important, the side that at present synthesis substituted aromatic amine is commonly used in pharmaceutical chemistry Method has following two methods：One kind is reduction amination；Another kind is coupling reaction.Buchwald-Hartwig coupling reactions are to close Into the important method of arylamine, there is cross-coupling reaction in amine with halogenated aromatic compound in the presence of palladium chtalyst and alkali.1999 Year, John F.Hartwig have studied catalytic effect of the palladium catalyst in halogenated hydrocarbons is aminated.In toluene is solvent, Pd (dba)2With part P (t-Bu)3It is catalyzed halogenated aromatic after complexing at ambient temperature anti-with the coupling of aromatic amine and fatty amine Should.
Also there are many scholars in recent years by activating phenolic hydroxyl group so as to phenolic hydroxyl group is converted into into amino.Patrick Phenolic hydroxyl group is first prepared into fluosulfonic acid ester by S.Hanley, and then obtains corresponding aromatic amine with amine reaction under Ni or Pd catalysis； Phenolic hydroxyl group is prepared into triflate and prepares corresponding aromatic amine with amine reaction again by Xu Gang；Also can by phenolic hydroxyl group first with 2,4,6- tri- chloro- 1, the reaction of 3,5- triazoles, then prepare corresponding aromatic amine with amine reaction in the presence of metallic catalyst.
However, considerably less with regard to the report of amino chromocor compound synthesis.Generally by amino before flavones parent nucleus is built Group is introduced, and the report that amino is directly introduced on flavones parent nucleus is even more rare.Sasaki et al. reports pass through 3-tosyl and 3- Mesyloxyflavones synthesizes 3-aminoflavones, and guesses that this reaction occurs by aziridine intermediate. Triflate and halide synthesizing amino flavones that Buchwald passes through flavones.And be with 7-triflyloxyflavone The amination yield of raw material is very low, and 5-isomer does not react.
Lemiere et al. is yellow by 7- triflates by palladium chtalyst using benzophenone imine as amino acid precursor Ketone synthesizes 7- amino flavones.Recently, although the substrate spectrum of metal catalytic aryl amination extends, this reaction is due to using high Expensive and sensitivity catalyst or part are used for the synthesis of arylamine flavones so as to largely limit it.Nucleophilic aromatic substitution (SNAr) reaction is another kind of approach for making aromatic aryl amination, but this reaction is frequently necessary to activate substrate, high temperature, highly basic The longer reaction time.Above-mentioned reaction must obtain and phenolic hydroxyl group is first changed into the intermediate easily left away, then urge in metal Corresponding amine is prepared into amine reaction under the conditions of change or Microwave-assisted firing, process is still complicated.
Above two steps are required for by the method that raw material prepares amino of phenol, i.e., first phenolic hydroxyl group must be lived with various reagents Change, then corresponding amine is prepared with amine reaction in the presence of metallic catalyst, and yield is medium.
For complicated polyphenol compound, such as flavone compound, the rarely found report of amino is introduced in its parent nucleus, it is most of All amino is introduced before flavones parent nucleus is built, the fragrant amido for so increasing synthesis of natural complexity polyphenol compound spreads out Biological complexity.Therefore exploration one directly directly can introduce amino as raw material with natural products on its aromatic rings is One necessary work.Although the use of transition-metal catalyst makes reaction efficiency be greatly increased, with This occurs in that some problems simultaneously, and as the transition metal used in course of reaction is expensive, catalyst recycling rate of waterused is low, leads Cause environmental pollution serious etc..Therefore green is explored, efficiently, economic synthetic method has important meaning to industrialization development.
The content of the invention
It is an object of the invention to overcome the shortcoming that said method is present, solution prepares at present the metal required for aromatic amine A kind of problem of catalyst and expensive starting materials, there is provided easy method for preparing aromatic amine, the method with phenol as raw material, without gold Metal catalyst catalytic manufacture of aromatic amines, environmental protection.
To solve above-mentioned technical problem, the present invention is achieved by the following technical solutions.
A kind of method for preparing aromatic amine compounds, comprises the following steps：Under inert gas shielding, by phenols chemical combination Thing and amine in molar ratio for 1: 2～40 mixed dissolutions in a solvent, 50～140 DEG C are reacted 6～15 hours, are prepared into corresponding Aromatic amine compound, then the aromatic amine compound that post-treated acquisition is pure；Its reaction equation is as follows：
Wherein, phenolic compound is as shown in formula R OH, amine such as structural formulaShown, aromatic amine compound is as tied Structure formulaIt is shown.
Described phenolic compound ROH is selected from substituted or unsubstituted phenol, naphthols, pyridine, flavones, quinones； Wherein, the substituent of phenol is C1-7Alkyl, C1-4The C of alkoxyl, halogen substiuted1-7Alkyl, halogen, nitro, acetyl group or nitrile Base；
Described amineIn, R1For H, hydroxyl, amino, benzyl, O- benzyls, N, N- dimethyl ethyls, C5-6Cycloalkanes Base, C1-6Alkyl,Substituted or unsubstituted phenyl；Wherein, m for 1-6 integer, n For the integer of 1-6；The substituent of described phenyl is C1-4Alkyl, C1-4The C of alkoxyl, halogen substiuted1-4Alkyl.
Preferably, the substituent of phenol is C1-4Alkyl, C1-3The C of alkoxyl, halogen substiuted1-4Alkyl, halogen, nitro, second Acyl group or itrile group.
It is further preferred that the substituent of phenol is C1-2Alkyl, C1-3The C that alkoxyl, F, Cl, Br replace1-2Alkyl, F, Cl, Br, nitro, acetyl group or itrile group.
Specifically, phenolic compound ROH can be selected from：Fortified phenol is p-nitrophenol, p-trifluoromethyl-phenol or 2- Acetyl phenol；Naphthols is 1- naphthols or beta naphthal；Flavone compound is 7- benzyl baicaleins, 6, the 7- dioxane roots of large-flowered skullcap Element, 6,7- dibenzyl baicaleins, scutellarin, 6,7- dioxane scutellarins, wogonin；Quinones is Isosorbide-5-Nitrae-two Anthraquinone or 1- naphthoquinones.
Preferably, R1For H, hydroxyl, amino, benzyl, O- benzyls, N, N- dimethyl ethyls, C5-6Cycloalkyl, C1-4Alkyl,Substituted or unsubstituted phenyl；Wherein, m is the integer of 1-3, and n is whole for 1-3's Number；The substituent of described phenyl is C1-3Alkyl, C1-3The C that alkoxyl, F, Cl, Br replace1-4Alkyl.
Described solvent is acetonitrile, DMF, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE, Isosorbide-5-Nitrae-dioxy Any one in six rings or toluene or its mixture.
Described phenolic compound and the mol ratio of amine is 1: 3～30.
The concentration of described phenolic compound is 0.1～10mol/L, preferably 0.3～5mol/L.
Described reaction temperature is preferably 50～150 DEG C, and the reaction time is preferably 3～24 hours.
Described post processing is：Reactant liquor is cooled to into room temperature, in pouring 3～15 times of water of reactant liquor into.If precipitation analysis Go out, then suction filtration carries out again silica gel column layer purifying to filter cake and obtains described aromatic amine product；If not there is Precipitation, to Organic reagent (ethyl acetate, ether, dichloromethane, the one of which of n-butanol) is wherein added to be extracted, organic phase is used full With saline solution washing, then it is dried with anhydrous sodium sulfate or magnesium sulfate, filtered, reduced pressure concentration, then carrying out silica gel column chromatography and is obtained Described aromatic amine product.Wherein, the eluent of silica gel column chromatography is that eluant, eluent is dichloromethane: methyl alcohol=100: 1-30: 1 (V/V)。
In the present invention, when phenolic compound ROH is selected from flavone compound, reactant liquor is cooled to room temperature and pours reactant liquor 3 into It is general to separate out precipitation in～15 times of water.Phenolic compound ROH is selected from substituted or unsubstituted phenol, naphthols, pyridine, quinones During compound, reactant liquor is cooled to room temperature and pours in 3～15 times of water of reactant liquor, generally requires and first carry out extraction processing.
Described inert gas is nitrogen.
The concrete operations of the method for the present invention：Under inert gas shielding, phenolic compound and amine in molar ratio for 1: 5～ 20 add in solvents, and the concentration of phenolic compound is 0.3～5mol/L, is stirred vigorously, control temperature at 50～150 DEG C, TLC plates Detection reaction process, treat to react completely, reactant liquor is cooled to into room temperature and is poured into water, with organic reagent (ethyl acetate, ether, The one of which of dichloromethane, n-butanol) extraction, organic phase anhydrous sodium sulfate or magnesium sulfate drying, reduced pressure concentration, silicagel column Chromatographic isolation, is prepared into corresponding aromatic amine compounds.
Compared to the prior art, effect of the invention：
(1) reaction system of the invention can make phenolic hydroxyl group be converted into aromatic amine compounds, reduce reactions steps, It is effectively reduced the three wastes three to put.
(2) raw material of the present invention is generally easy to get, simple to operate, wide application range of substrates, under the conditions of without catalyst i.e. Phenolic compound can be obtained the corresponding aromatic amine compound of higher yields by nucleophilic addition, it is adaptable to industrialize Production.
(3) phenolic compound can be obtained corresponding amine, inhomogeneity by the present invention by single step reaction through single step reaction The phenol in type and different replacement sites can smoothly obtain corresponding aromatic amine.Importantly, the present invention is successfully applied By baroque natural products, such as flavones, quinones is prepared into corresponding aminated compounds.
(4) present invention allows there is water in reaction system, can be with ammoniacal liquor or hydrazine hydrate as substrate, using ammonium chloride as urging Agent and cosolvent, successfully prepare the primary ammoniac compounds of one-level fragrance from phenolic hydroxyl group.
(5) present invention has preferable selectivity to phenolic hydroxyl group, even if there is halogen atom in substrate, also not interfere with this anti- The generation answered.
Specific embodiment
For a better understanding of the present invention, below will by embodiment, the present invention is described further, following examples The description present invention is only used for, without limitation on the present invention described in detail in claims.
Embodiment 1
The following N- normal butane base -4- nitroanilines of preparation structure
P-nitrophenol (209mg, 1.5mmol) is dissolved in DMF (2mL), positive fourth is added dropwise thereto Amine (2.9mL, 30mmol), reacts 9 hours under nitrogen protective condition by 120 DEG C, is cooled to room temperature.Pour reactant liquor into 16mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- normal butanes base -4- nitre of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V) Base aniline, yellow liquid, its yield is 64%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：7.96 (d, J=8.9Hz, 2H), 7.27 (t, J=3.1Hz, 1H ,-NH), 6.59 (d, J=8.9Hz, 2H), 3.10 (q, J=8.8Hz, 2H), 1.52 (m, 2H), 1.36 (m, 2H), 0.88 (t, J=8.8Hz, 3H ,-CH3)；MS (ESI) m/z=193.1 [M-H]-； HRMS(ESI)C10H13N2O2[M-H]-：Theoretical value 193.0983, measured value 193.0913.
Embodiment 2
The following N- ethylamino- -4- nitroanilines of preparation structure
P-nitrophenol (209mg, 1.5mmol) is dissolved in 1-METHYLPYRROLIDONE (3mL), anhydrous second is added dropwise thereto Diamines (1.5mL, 23mmol), reacts 8 hours under nitrogen protective condition by 120 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL In water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- ethylamino-s -4- nitros of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Aniline, yellow liquid, its yield is 71%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：7.97 (d, J =8.9Hz, 2H), 7.31 (t, J=3.1Hz, 1H ,-NH), 6.62 (d, J=8.9Hz, 2H), 3.13 (q, J=6.2Hz, 2H), 2.72 (t, J=6.2Hz, 2H), 2.07 (br s, 2H ,-NH2)；MS (ESI) m/z=180.1 [M-H]-；HRMS(ESI) C8H10N3O2[M-H]-：Theoretical value 180.0779, measured value 180.0803.
Embodiment 3
The following N- benzyl -4- nitroanilines of preparation structure
P-nitrophenol (209mg, 1.5mmol) is dissolved in 1-METHYLPYRROLIDONE (2mL), benzylamine is added dropwise thereto (4.1mL, 38mmol), reacts 8 hours under nitrogen protective condition by 125 DEG C, is cooled to room temperature.Reactant liquor is poured in 16mL water, Dichloromethane extracts (3 × 5mL), and organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, revolving, soon The isolated product N- benzyls -4- nitroanilines of fast silica gel column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V), it is yellow Color oily, its yield is 58%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：8.07 (d, J= 8.7Hz, 2H), 7.35 (m, 5H), 6.57 (d, J=8.7Hz, 2H), 4.97 (br s, 1H ,-NH), 4.44 (d, J=6.1Hz, 2H)；MS (ESI) m/z=227.1 [M-H]-；HRMS(ESI)C13H11N2O2[M-H]-：Theoretical value 227.0826, measured value 227.0802。
Embodiment 4
The following N- ethanol base -4- nitroanilines of preparation structure
P-nitrophenol (209mg, 1.5mmol) is dissolved in dimethyl sulfoxide (DMSO) (3mL), monoethanolamine is added dropwise thereto (1.8mL, 30mmol), reacts 10 hours under nitrogen protective condition by 130 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- ethanol base -4- nitros of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Aniline, yellow liquid, its yield is 69%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：7.97 (d, J =8.9Hz, 2H), 7.42 (t, J=5.2Hz, 1H ,-NH), 6.67 (d, J=8.9Hz, 2H), 4.92 (brs, 1H ,-OH), 3.57 (t, J=6.0Hz, 2H), 3.22 (q, J=6.0Hz, 2H)；MS (ESI) m/z=181.1 [M-H]-；HRMS(ESI)C8H9N2O3 [M-H]-：Theoretical value 181.0619, measured value 181.0607.
Embodiment 5
The following N- benzyl -4- 5-trifluoromethylanilines of preparation structure
P-trifluoromethyl-phenol (209mg, 1.5mmol) is dissolved in 1-METHYLPYRROLIDONE (3mL), benzyl is added dropwise thereto Amine (2.5mL, 23mmol), reacts 7 hours under nitrogen protective condition by 120 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- benzyls -4- fluoroforms of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) Base aniline, yellow oily, its yield is 49%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：8.78 (t, J=6.0Hz, 1H ,-NH), 7.76 (d, J=8.8Hz, 2H), 7.30 (m, 4H), 7.29 (m, 1H), 6.79 (d, J= 8.8Hz, 2H), 4.44 (d, J=6.0Hz, 2H)；MS (ESI) m/z=250.1 [M-H]-；HRMS(ESI)C14H11F3N[M-H]-： Theoretical value 250.0849, measured value 250.0793.
Embodiment 6
The following N- propyl alcohol base -4- nitroanilines of preparation structure
P-nitrophenol (209mg, 1.5mmol) is dissolved in dimethyl sulfoxide (DMSO) (3mL), 3- aminopropanols are added dropwise thereto (2.3mL, 30mmol), reacts 9 hours under nitrogen protective condition by 130 DEG C, is cooled to room temperature.Reactant liquor is poured in 24mL water, Dichloromethane extracts (3 × 5mL), and organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, revolving, soon The isolated product N- propyl alcohol base -4- nitroanilines of fast silica gel column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V), Yellow liquid, its yield is 57%.The characterize data of product：1H NMR (300MHz, CDCl3, δ ppm)：8.00 (d, J= 8.2Hz, 2H), 6.49 (d, J=8.2Hz, 2H), 5.35 (br s, 1H ,-NH-), 3.81 (t, J=6.4Hz, 2H ,-OCH2-), 3.35 (m, 2H), 2.68 (br s, 1H ,-OH), 1.90 (t, J=6.4Hz, 2H ,-NCH2-)；13C NMR (75MHz, CDCl3, δ ppm)：153.4,136.6,126.1,110.4,60.3,40.6,30.6；MS (ESI) m/z=195.1 [M-H]-；HRMS(ESI) C9H11N2O3[M-H]-：Theoretical value 195.0775, measured value 195.0716.
Embodiment 7
Following N- ethanol base -6 of preparation structure, 7- dibenzyl baicaleins
6,7- dibenzyl baicaleins (450mg, 1mmol) is dissolved in DMF (3mL), is added dropwise thereto Monoethanolamine (1.2mL, 20mmol), reacts 9 hours under helium protective condition by 135 DEG C, is cooled to room temperature.Reactant liquor is poured into In 24mL frozen water, a large amount of dark yellow solids are separated out, crude product Jing Flash silica column chromatographies (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) isolated product N- ethanol base -6,7- dibenzyl baicaleins, yellow powder, its yield is 57%.The sign number of product According to：1H NMR (300MHz, DMSO-d6, δ ppm)：8.11 (dd, J=8.2Hz, 2.1Hz, 2H), 7.58 (m, 3H), 7.41 (m, 6H), 7.31 (m, 2H), 7.26 (m, 2H), 7.17 (s, 1H), 6.35 (s, 1H), 5.13 (s, 2H ,-OCH2-), 4.96 (s, 2H ,- OCH2-), 3.74 (t, J=6.1Hz, 2H ,-OCH2-), 3.48 (m, 2H ,-NCH2-)；13C NMR (75MHz, DMSO-d6, δ ppm)：167.4,161.4,159.6,156.8,151.4,139.3,137.5,134.8,132.4,131.3,129.5,128.8, 128.4,128.3,128.2,127.9,127.7,126.9,101.4,93.5,84.7,73.0,70.1,58.3,45.6；MS (ESI) m/z=492.1 [M-H]-；HRMS(ESI)C31H26NO5[M-H]-：Theoretical value 492.1816, measured value 492.1895.
Embodiment 8
The following N- of preparation structure (N, N- dimethyl) ethyl -7- benzyl baicaleins
7- benzyl baicaleins (360mg, 1mmol) is dissolved in DMF (3mL), N, N- are added dropwise thereto Dimethyl-ethylenediamine (1.4mL, 15mmol), reacts 8 hours under helium protective condition by 120 DEG C, is cooled to room temperature.By reactant liquor In pouring 24mL frozen water into, a large amount of dark yellow solids are separated out, and (eluant, eluent is dichloromethane to crude product Jing Flash silica column chromatographies: methyl alcohol Isolated product N- (N, N- dimethyl) ethyl -7- benzyl baicalein, yellow powder, its yield be 53%=40: 1V/V). The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：13.81 (s, 1H ,-OH), 8.08 (d, J=6.1Hz, 2H), 7.46 (d, J=6.1Hz, 2H), 7.37 (t, J=6.1Hz, 2H), 7.32 (m, 1H), 7.10 (s, 1H), 6.34 (s, 1H), 5.16 (s, 2H ,-OCH2-), 3.70 (t, J=6.1Hz, 2H ,-NCH2-), 2.53 (m, 2H ,-NCH2-), 2.21 (s, 6H, 2 ×- CH3)；13C NMR (75MHz, DMSO-d6, δ ppm)：162.1,161.4,158.8,148.2,146.9,137.3,133.9, 131.8,130.9,128.9,128.3,127.6,127.4,126.4,99.0,92.4,85.1,69.8,57.5,45.0,40.5； MS (ESI) m/z=429.1 [M-H]-；HRMS(ESI)C26H25N2O4[M-H]-：Theoretical value 429.1820, measured value 429.1857.
Embodiment 9
Following 5-N- benzyl -6 of preparation structure, 7- epoxy ethyl scutellarins
6,7- epoxy ethyl scutellarins (312mg, 1mmol) is dissolved in DMF (3mL), thereto Benzylamine (1.6mL, 15mmol) is added dropwise, 120 DEG C, is reacted 8 hours under helium protective condition, be cooled to room temperature.Reactant liquor is poured into In 24mL frozen water, a large amount of dark yellow solids are separated out, crude product Jing Flash silica column chromatographies (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) isolated product 5-N- benzyl -6,7- epoxy ethyl scutellarins, yellow powder, its yield is 61%.The table of product Levy data：1H NMR (300MHz, DMSO-d6, δ ppm)：7.95 (d, J=8.1Hz, 2H), 7.41 (m, 4H), 7.37 (t, J= 6.1Hz, 2H), 7.33 (m, 1H), 7.32 (m, 1H ,-NH-), 7.04 (s, 1H), 6.92 (d, J=8.1Hz, 2H), 5.98 (s, 1H), 4.90 (d, J=6.0Hz, 2H), 4.23 (m, 2H ,-OCH2-), 4.11 (m, 2H ,-OCH2-)；MS (ESI) m/z=400.1 [M-H]-；HRMS(ESI)C24H18NO5[M-H]-：Theoretical value 400.1190, measured value 400.1237.
Embodiment 10
Following 5-N- ethanol base -6 of preparation structure, 7- epoxy ethyl baicaleins
6,7- epoxy ethyl baicaleins (296mg, 1mmol) is dissolved in DMF (3mL), is dripped thereto Plus monoethanolamine (1.5mL, 25mmol), 130 DEG C, react 11 hours under helium protective condition, it is cooled to room temperature.Reactant liquor is poured into In 24mL frozen water, a large amount of dark yellow solids are separated out, crude product Jing Flash silica column chromatographies (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) isolated product 5-N- ethanol base -6,7- epoxy ethyl baicaleins, yellow powder, its yield is 73%.The table of product Levy data：1H NMR (300MHz, DMSO-d6, δ ppm)：8.10 (d, J=6.2Hz, 2H), 7.59 (m, 3H), 7.15 (s, 1H), (6.04 s, 1H), 5.05 (br s, 1H ,-OH), 4.25 (m, 2H), 4.14 (m, 2H), 3.73 (m, 2H), 3.67 (m, 2H)；13C NMR (75MHz, DMSO-d6, δ ppm)：160.8,159.2,148.2,147.8,131.9,131.0,130.9,129.0, 126.4,99.5,92.7,86.3,64.7,63.0,59.8,45.1；MS (ESI) m/z=338.1 [M-H]-；HRMS(ESI) C19H16NO5[M-H]-：Theoretical value 338.1034, measured value 338.1093.
Embodiment 11
Following 5-N- normal propyl alcohols base -6 of preparation structure, 7- epoxy ethyl baicaleins
6,7- epoxy ethyl baicaleins (296mg, 1mmol) is dissolved in DMF (3mL), is dripped thereto Plus 3- aminopropanols (1.5mL, 20mmol), 125 DEG C, react 10 hours under helium protective condition, it is cooled to room temperature.By reactant liquor In pouring 24mL frozen water into, a large amount of dark yellow solids are separated out, and (eluant, eluent is dichloromethane to crude product Jing Flash silica column chromatographies: methyl alcohol Isolated product 5-N- normal propyl alcohol base -6=50: 1V/V), 7- epoxy ethyl baicaleins, yellow powder, its yield is 69%. The characterize data of product：1H NMR (300MHz, CDCl3δppm)：7.61 (d, J=6.2Hz, 2H), 7.34 (m, 3H), 6.30 (s, 1H), 5.66 (s, 1H), 4.53 (br s, 1H ,-OH), 4.07 (m, 2H), 4.05 (m, 2H), 3.74 (m, 2H), 3.43 (m, 2H), 1.87 (m, 2H)；13C NMR (75MHz, CDCl3, δ ppm)：162.9,161.2,158.6,147.9,147.8,131.1, 131.0,130.4,128.2,125.6,99.5,90.7,87.1,64.4,63.0,57.8,38.9,31.1；MS (ESI) m/z= 352.1[M-H]-；HRMS(ESI)C20H18NO5[M-H]-：Theoretical value 352.1190, measured value 352.1241.
Embodiment 12
Following 5-N- normal propyl alcohols base -6 of preparation structure, 7- epoxy ethyl baicaleins
6,7- epoxy ethyl baicaleins (296mg, 1mmol) is dissolved in 1-METHYLPYRROLIDONE (3mL), is added dropwise thereto N, N- dimethyl-ethylenediamine (1.4mL, 15mmol), reacts 9 hours under helium protective condition by 130 DEG C, is cooled to room temperature.Will be anti- Liquid is answered to pour in 24mL frozen water, a large amount of dark yellow solids are separated out, crude product Jing Flash silica column chromatographies (eluant, eluent is dichloromethane: Methyl alcohol=50: 1V/V) isolated product 5-N- normal propyl alcohols base -6,7- epoxy ethyl baicaleins, yellow powder, its yield is 63%.The characterize data of product：1H NMR (300MHz, CDCl3δppm)：8.18 (br s, 1H ,-NH-), 7.89 (d, J= 6.2Hz, 2H), 7.53 (m, 3H), 6.57 (s, 1H), 6.04 (s, 1H), 4.29 (m, 4H), 3.63 (t, J=6.1Hz, 2H), 2.70 (t, J=6.1Hz, 2H), 2.36 (s, 6H, 2 ×-CH3)；HRMS(ESI)C21H21N2O4[M-H]-：Theoretical value 365.1507, Measured value 365.1573.
Embodiment 13
The following N- ethylamino-s-acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in 1-METHYLPYRROLIDONE (3mL), are added dropwise thereto anhydrous Ethylenediamine (1.5mL, 23mmol), reacts 8 hours under nitrogen protective condition by 120 DEG C, is cooled to room temperature.Reactant liquor is poured into In 23mL water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, mistake Filter, revolving, the isolated product N- ethylamino-s-second of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Anilid, yellow liquid, its yield is 87%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)： 16.01 (br s, 1H ,-NH), 7.66 (m, 1H, Ar-H), 7.28 (m, 1H, Ar-H), 6.76 (m, 2H, Ar-H), 3.94 (m, 2H), 3.31 (m, 2H), 2.41 (s, 3H)；13C NMR (75MHz, CDCl3, δ ppm)：173.1,163.0,132.3,131.9, 117.8,116.9,49.4,39.5,14.6；MS (ESI) m/z=177.1 [M-H]-。
Embodiment 14
The following N- ethanol base -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in dimethyl sulfoxide (DMSO) (3mL), monoethanolamine is added dropwise thereto (1.8mL, 30mmol), reacts 10 hours under nitrogen protective condition by 130 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- ethanol base -2- acetyl of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Base aniline, yellow liquid, its yield is 83%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：16.58 (br s, 1H ,-NH), 7.60 (d, J=8.2Hz, 1H), 7.24 (t, J=8.2Hz, 1H), 6.74 (m, 2H), 4.85 (br s, 1H), 3.67 (m, 2H), 3.63 (m, 2H), 2.34 (s, 3H)；13C NMR (75MHz, CDCl3, δ ppm)：173.3,165.1, 132.8,129.1,118.9,116.6,61.1,51.4,14.8；MS (ESI) m/z=178.1 [M-H]-。
Embodiment 15
The following N- propyl alcohol base -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in dimethyl sulfoxide (DMSO) (3mL), 3- aminopropans are added dropwise thereto Alcohol (2.3mL, 30mmol), reacts 9 hours under nitrogen protective condition by 130 DEG C, is cooled to room temperature.Pour reactant liquor into 24mL water In, ethyl acetate extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- propyl alcohol base -2- acetyl of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) Base aniline, yellow liquid, its yield is 84%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：7.59 (d, J=8.2Hz, 1H), 7.25 (t, J=8.2Hz, 1H), 6.75 (m, 2H), 3.62 (m, 2H), 3.57 (m, 2H), 2.34 (s, 3H), 1.85 (t, J=10.1Hz, 1H)；13C NMR (75MHz, CDCl3, δ ppm)：173.0,165.2,132.8,129.0, 118.9,118.8,116.6,58.7,45.3,33.4,14.5；MS (ESI) m/z=192.1 [M-H]-；
Embodiment 16
The following N- cyclohexyl -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in dimethyl sulfoxide (DMSO) (3mL), cyclohexylamine is added dropwise thereto (2.2mL, 20mmol), reacts 9 hours under nitrogen protective condition by 130 DEG C, is cooled to room temperature.Reactant liquor is poured in 24mL water, Ethyl acetate extracts (3 × 5mL), and organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, revolving, soon The isolated product N- cyclohexyls -2- acetylbenzenes of fast silica gel column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) Amine, yellow oily liquid, its yield is 80%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：16.07 (br s, 1H ,-NH), 7.59 (d, J=8.2Hz, 1H), 7.25 (t, J=8.2Hz, 1H), 6.75 (m, 2H), 3.73 (m, 1H), 2.36 (s, 3H), 1.78 (m, 2H), 1.72 (m, 2H), 1.56 (m, 1H), 1.35 (m, 5H)；13C NMR (75MHz, DMSO-d6, δ ppm)：170.4,165.1,132.6,129.0,119.2,118.7,116.6,56.2,33.5,25.6,24.1,14.5；MS (ESI) m/z=216.1 [M-H]-；
Embodiment 17
The following N- ethyl -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in 1-METHYLPYRROLIDONE (3mL), ethamine is added dropwise thereto (2.6mL, 40mmol), reacts 10 hours under nitrogen protective condition by 60 DEG C, is cooled to room temperature.Reactant liquor is poured in 23mL water, Dichloromethane extracts (3 × 5mL), and organic phase saturated aqueous common salt (2 × 4mL) is washed, and anhydrous magnesium sulfate is dried, filters, revolving, soon The isolated product N- ethyls -2- acetyl group aniline of fast silica gel column chromatography (eluant, eluent is dichloromethane: methyl alcohol=200: 1V/V), Yellow oily, its yield is 57%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：16.65 (br s, 1H ,-NH), 7.58 (m, 1H), 7.24 (t, J=8.2Hz, 1H), 6.77 (m, 2H), 3.54 (q, J=9.2Hz, 1H), 2.32 (s, 3H), 1.27 (t, J=9.2Hz, 1H)；MS (ESI) m/z=162.1 [M-H]-.
Embodiment 18
The following N- isopropyl -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (3mL), are added dropwise thereto different Propylamine (2.9mL, 35mmol), reacts 10 hours under nitrogen protective condition by 65 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL In water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, and anhydrous magnesium sulfate is dried, filters, rotation Steam, the isolated product N- isopropyls -2- acetyl of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=200: 1V/V) Base aniline, yellow oily, its yield is 60%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：16.82 (br s, 1H ,-NH), 7.37 (d, J=8.2Hz, 1H), 7.15 (t, J=8.2Hz, 1H), 6.77 (d, J=8.2Hz, 1H), 6.62 (d, J=8.2Hz, 1H), 3.88 (m, 1H), 2.30 (s, 3H), 1.20 (d, J=9.2Hz, 6H)；MS (ESI) m/z= 176.1[M-H]-.
Embodiment 19
The following N- normal butane base -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (2mL), are added dropwise thereto just Butylamine (2.9mL, 30mmol), reacts 9 hours under nitrogen protective condition by 120 DEG C, is cooled to room temperature.Pour reactant liquor into 16mL In water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- normal butanes base -2- second of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V) Anilid, yellow liquid, its yield is 64%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)： 16.08 (br s, 1H ,-NH), 7.61 (d, J=8.2Hz, 1H), 7.26 (t, J=8.2Hz, 1H), 6.74 (m, 2H), 3.55 (t, J=6.2Hz, 2H), 2.35 (s, 3H), 1.64 (m, 2H), 1.43 (m, 2H), 0.94 (t, J=9.2Hz, 3H)；13C NMR (75MHz, DMSO-d6, δ ppm)：172.7,165.2,132.8,129.0,118.9,116.5,48.2,32.3,20.4,14.1； MS (ESI) m/z=190.1 [M-H]-.
Embodiment 20
The following 2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (2mL), ammonia is added dropwise thereto Water (1.7mL, 45mmol), reacts 12 hours under nitrogen protective condition by 55 DEG C, is cooled to room temperature.Pour reactant liquor into 16mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product 2- acetyl group aniline of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V), it is yellow Color powder, its yield is 58%.The characterize data of product：1H NMR (300MHz, CDCl3, δ ppm)：15.13 (br s, 1H ,- NH), 9.21 (br s, 1H ,-NH), 7.51 (d, J=8.2Hz, 1H), 7.37 (t, J=8.2Hz, 1H), 7.01 (d, J= 8.2Hz, 1H), 6.84 (t, J=8.2Hz, 1H), 2.52 (s, 3H)；13C NMR (75MHz, CDCl3, δ ppm)：178.2, 163.4,136.4,133.3,118.4,117.5,26.1；MS (ESI) m/z=134.1 [M-H]-.
Embodiment 21
The following 2- phenacethydrazines of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (2mL), water is added dropwise thereto Hydrazine (2.2mL, 45mmol) is closed, 70 DEG C, is reacted 12 hours under nitrogen protective condition, be cooled to room temperature.Pour reactant liquor into 16mL In water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product 2- phenacethydrazines of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=40: 1V/V), it is yellow Color powder, its yield is 61%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：13.44 (br s, 1H ,- NH), 7.40 (d, J=8.2Hz, 1H), 7.15 (t, J=8.2Hz, 1H), 6.85 (m, 2H), 6.58 (br s, 2H ,-NH2), 2.16 (s, 3H)；13C NMR (75MHz, DMSO-d6, δ ppm)：158.6,149.5,129.2,126.9,120.9,118.6, 116.9,11.2；MS (ESI) m/z=149.1 [M-H]-.
Embodiment 22
The following 2- acetylbenzene azanols of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (4mL), salt is added dropwise thereto Sour azanol (2.4g, 35mmol), reacts 11 hours under nitrogen protective condition by 70 DEG C, is cooled to room temperature.Pour reactant liquor into 16mL In water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product 2- acetylbenzene azanols of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=40: 1V/V), Yellow powder, its yield is 57%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：14.57 (br s, 1H ,-NH), 7.43 (d, J=8.2Hz, 1H), 7.12 (t, J=8.2Hz, 1H), 6.81 (m, 2H), 2.15 (s, 3H)；MS(ESI) M/z=150.1 [M-H]-.
Embodiment 23
The following O- benzyl -2- acetylbenzene azanols of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (3mL), O- is added dropwise thereto Benzyl hydroxylamine (4.1mL, 35mmol), reacts 9 hours under nitrogen protective condition by 115 DEG C, is cooled to room temperature.Reactant liquor is poured into In 16mL water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, mistake Filter, revolving, the isolated product O- benzyls -2- second of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) Acyl group phenylhydroxyamine, yellow solid, its yield is 59%.The characterize data of product：1H NMR (300MHz, CDCl3, δ ppm)： 11.20 (br s, 1H), 7.45 (m, 8H), 6.98 (d, J=8.2Hz, 1H), 5.21 (s, 1H), 2.40 (s, 3H)；13C NMR (75MHz, CDCl3, δ ppm)：158.8,157.9,137.6,130.8,128.6,128.5,128.3,127.6,119.0, 117.4,11.8；MS (ESI) m/z=240.1 [M-H]-；
Embodiment 24
The following N- normal butane base -2- acetyl group -5- bromanilines of preparation structure
2- acetyl group -5- bromophenols (322mg, 1.5mmol) is dissolved in DMF (2mL), thereto N-butylamine (2.9mL, 30mmol) is added dropwise, 110 DEG C, is reacted 9 hours under nitrogen protective condition, be cooled to room temperature.Reactant liquor is fallen In entering 16mL water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, Filter, rotate, the isolated product N- normal butanes of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V) Base -2- acetyl group -5- bromanilines, yellow powder, its yield is 69%.The characterize data of product：1H NMR (300MHz, DMSO- d6, δ ppm)：17.21 (br s, 1H ,-NH), 7.47 (m, 1H), 6.87 (m, 1H), 6.71 (m, 1H), 3.55 (t, J=6.2Hz, 2H), 2.49 (s, 3H), 1.62 (m, 2H), 1.39 (m, 2H), 0.91 (t, J=9.2Hz, 3H)；13C NMR (75MHz, DMSO- d6, δ ppm)：172.8,168.8,130.3,126.6,122.3,117.4,116.2,46.3,31.2,30.5,19.1；MS (ESI) m/z=269.1 [M-H]-.
Embodiment 25
The following N- p-methoxyphenyl -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (3mL), it is right to be added thereto to Aminoanisole (1.8g, 15mmol), reacts 9 hours under nitrogen protective condition by 115 DEG C, is cooled to room temperature.Reactant liquor is poured into In 16mL water, ethyl acetate extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, mistake Filter, revolving, the isolated product N- of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V) is to methoxyl group Phenyl -2- acetyl group aniline, yellow solid, its yield is 73%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：15.05 (br s, 1H), 7.62 (d, J=8.2Hz, 1H), 7.41 (m, 1H), 7.05 (d, J=8.2Hz, 1H), 6.94 (m, 5H), 3.85 (s, 3H), 2.37 (s, 3H)；MS (ESI) m/z=240.1 [M-H]-；
Embodiment 26
The following N- p-fluorophenyl -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in DMF (3mL), it is right to be added thereto to Fluoroaniline (950 μ L, 10mmol), reacts 9 hours under nitrogen protective condition by 115 DEG C, is cooled to room temperature.Reactant liquor is poured into In 16mL water, ethyl acetate extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, mistake Filter, revolving, the isolated product N- of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V) is to fluorobenzene Base -2- acetyl group aniline, yellow solid, its yield is 58%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：12.33 (s, 1H), 8.02 (d, J=8.2Hz, 1H), 7.69 (t, J=8.2Hz, 1H), 7.40 (t, J=8.2Hz, 1H), 7.19 (m, 5H), 2.80 (s, 3H)；13C NMR (75MHz, DMSO-d6, δ ppm)：172.9,161.6,133.4,131.6, 129.9,123.4,123.3,119.4,118.5,117.9,116.2,115.9,17.2；MS (ESI) m/z=228.1 [M-H]-；
Embodiment 27
The following N- p-isopropyl phenyl -2- acetyl group aniline of preparation structure
2- acetyl phenols (267mg, 1.5mmol) are dissolved in dimethyl sulfoxide (DMSO) (4mL), p-isopropyl is added thereto to Aniline (950 μ L, 10mmol), reacts 9 hours under nitrogen protective condition by 115 DEG C, is cooled to room temperature.Pour reactant liquor into 16mL In water, ethyl acetate extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- p-isopropyl phenyl of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V)- 2- acetyl group aniline, yellow solid, its yield is 67%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)： 14.74 (s, 1H ,-ArNH-), 7.73 (d, J=8.2Hz, 1H), 7.39 (t, J=8.2Hz, 1H), 7.26 (m, 2H), 6.91 (m, 4H), 2.88 (m, 1H), 2.32 (s, 3H), 1.21 (d, J=6.1Hz, 6H)；13C NMR (75MHz, DMSO-d6, δ ppm)： 171.7,161.4,144.9,144.1,132.9,129.5,126.8,121.2,119.5,118.1,117.4,32.9,23.8, 16.8；MS (ESI) m/z=252.1 [M-H]-；
Embodiment 28
The following 2- acetyl group -5- bromanilines of preparation structure
2- acetyl group -5- bromophenols (322mg, 1.5mmol) is dissolved in DMF (3mL), thereto Ammoniacal liquor (1.7mL, 45mmol) is added dropwise, 60 DEG C, is reacted 9 hours under nitrogen protective condition, be cooled to room temperature.Reactant liquor is poured into In 16mL water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 5mL) is washed, anhydrous sodium sulfate drying, mistake Filter, revolving, the isolated product 2- acetyl group -5- of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) Bromaniline, yellow oily, its yield is 56%.The characterize data of product：1H NMR (300MHz, CDCl3, δ ppm)：15.14(br S, 1H), 9.21 (br s, 1H ,-NH), 7.37 (d, J=8.1Hz, 1H), 6.77 (s, 1H), 6.49 (d, J=8.1Hz, 1H), 2.48 (s, 3H)；13C NMR (75MHz, CDCl3, δ ppm)：177.3,175.4,133.0,132.4,130.2,125.7, 115.5,114.1,20.5；MS (ESI) m/z=134.1 [M-H]-.
Embodiment 29
The following 1- ethylenediamine base anthraquinones of preparation structure
1- hydroxyl naphthoquinones (174mg, 1mmol) are dissolved in 1-METHYLPYRROLIDONE (3mL), 3- aminopropans are added dropwise thereto Alcohol (2.3mL, 30mmol), reacts 8 hours under nitrogen protective condition by 60 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product 1- ethylenediamines base anthraquinone of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V), Blue oily, its yield is 81%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：11.47 (br s, 1H ,-NH), 7.71 (t, J=8.1Hz, 1H), 7.62 (t, J=8.1Hz, 1H), 7.48 (d, J=8.1Hz, 1H), 7.20 (d, J =8.1Hz, 1H), 5.75 (s, 1H), 4.68 (t, J=6.1Hz, 1H), 3.49 (m, 2H), 3.21 (m, 2H), 1.74 (m, 2H)； MS (ESI) m/z=230.1 [M-H]-.
Embodiment 30
The following 1- ethylenediamine base -4- hydroxy-anthraquiones of preparation structure
Isosorbide-5-Nitrae-dihydroxy anthraquinone (240mg, 1mmol) is dissolved in 1-METHYLPYRROLIDONE (3mL), is added dropwise thereto anhydrous Ethylenediamine (1.5mL, 23mmol), reacts 8 hours under nitrogen protective condition by 55 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL In water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- ethylamino-s-acetyl group of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Aniline, navy blue oily, its yield is 69%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：15.53 (s, 1H ,-OH), 10.56 (br s, 1H ,-NH), 8.20 (m, 2H), 8.02 (s, 1H), 7.77 (m, 2H), 6.11 (s, 1H), 3.58 (m, 2H ,-NHCH2-), 3.46 (m, 2H ,-NHCH2-)；MS (ESI) m/z=281.1 [M-H]-。
Embodiment 31
The following 1- ring amine base -4- hydroxy-anthraquiones of preparation structure
Isosorbide-5-Nitrae-dihydroxy anthraquinone (240mg, 1mmol) is dissolved in 1-METHYLPYRROLIDONE (3mL), hexamethylene is added dropwise thereto Amine (2.3mL, 23mmol), reacts 8 hours under nitrogen protective condition by 55 DEG C, is cooled to room temperature.Pour reactant liquor into 23mL water In, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, filtration, rotation Steam, the isolated product N- ethylamino-s-acetyl group of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Aniline, navy blue oily, its yield is 69%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：13.5 (s, 1H ,-OH), 10.51 (d, J=6.1Hz, 1H ,-NH), 8.27 (m, 2H), 7.94 (m, 1H), 7.58 (d, J=6.1Hz, 1H), 7.35 (d, J=6.1Hz, 1H), 3.79 (m, 1H), 2.00 (m, 2H), 1.73 (m, 2H), 1.60 (m, 1H), 1.41 (m, 5H)；MS (ESI) m/z=310.1 [M-H]-。
Embodiment 32
The following N- ethanol base -2- acetyl group -5-O- propyl group aniline of preparation structure
2- acetyl group -5-O- propylphenols (207mg, 1mmol) is dissolved in dimethyl sulfoxide (DMSO) (3mL), is added dropwise thereto Monoethanolamine (1.8mL, 30mmol), reacts 10 hours under nitrogen protective condition by 130 DEG C, is cooled to room temperature.Reactant liquor is poured into In 23mL water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, mistake Filter, revolving, the isolated product N- ethanol base -2- of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=30: 1V/V) Acetyl group -5-O- propyl group aniline, yellow liquid, its yield is 85%.The characterize data of product：1H NMR (300MHz, DMSO- d6, δ ppm)：16.84 (br s, 1H ,-NH), 7.45 (d, J=8.2Hz, 1H), 7.16 (m, 2H), 4.95 (br s, 1H ,-OH), 4.85 (br s, 1H), 3.88 (m, 2H), 3.66 (m, 2H), 3.62 (m, 2H), 2.34 (s, 3H), 1.71 (m, 2H), 0.97 (t, J =6.2Hz, 3H),；13C NMR (75MHz, DMSO-d6, δ ppm)：172.6,171.8,163.5,130.7,111.7,104.8, 103.0,69.1,60.8,49.4,22.4,14.5,10.7；MS (ESI) m/z=236.1 [M-H]-。
Embodiment 33
The following N- p-methylphenyl -2- acetyl group -5- bromanilines of preparation structure
2- acetyl group -5- bromophenols (322mg, 1.5mmol) is dissolved in DMF (4mL), thereto Para-totuidine (1.1mL, 10mmol) is added dropwise, 110 DEG C, is reacted 9 hours under nitrogen protective condition, be cooled to room temperature.By reactant liquor In pouring 16mL water into, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, and anhydrous sodium sulfate is done Dry, filtration, revolving, Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=100: 1V/V) isolated product N- pair Tolyl -2- acetyl group -5- bromanilines, yellow powder, its yield is 70%.The characterize data of product：1H NMR (300MHz, CDCl3, δ ppm)：15.33 (s, 1H ,-NH), 7.44 (d, J=8.2Hz, 1H), 7.24 (d, J=2.1Hz, 1H), 7.22 (d, J =8.2Hz, 2H), 7.00 (dd, J=8.2Hz, J=2.1Hz, 1H), 7.85 (d, J=8.2Hz, 2H), 2.42 (s, 3H), 2.34 (s, 3H)；13C NMR (75MHz, CDCl3, δ ppm)：170.7,163.2,143.6,134.8,129.9,129.7,126.8, 121.4,121.3,118.7,21.0,16.9；MS (ESI) m/z=302.1 [M-H]-.
Embodiment 34
The following 2- phenacethydrazines of preparation structure
2- acetyl group -5- bromophenols (322mg, 1.5mmol) is dissolved in DMF (4mL), thereto Hydrazine hydrate (2.2mL, 45mmol) is added dropwise, 70 DEG C, is reacted 12 hours under nitrogen protective condition, be cooled to room temperature.Reactant liquor is fallen In entering 16mL water, dichloromethane extraction (3 × 5mL), organic phase saturated aqueous common salt (2 × 4mL) is washed, anhydrous sodium sulfate drying, Filter, rotate, the isolated product 2- acetyl group of Flash silica column chromatography (eluant, eluent is dichloromethane: methyl alcohol=40: 1V/V) Phenylhydrazine, yellow powder, its yield is 57%.The characterize data of product：1H NMR (300MHz, DMSO-d6, δ ppm)：13.62(br S, 1H ,-NH), 7.33 (d, J=8.2Hz, 1H), 6.98 (m, 1H), 6.94 (d, J=2.1Hz, 1H), 6.69 (br s, 2H ,- NH2), 2.13 (s, 3H)；13C NMR (75MHz, DMSO-d6, δ ppm)：169.0,147.6,127.9,120.9,119.7, 118.9,11.0；MS (ESI) m/z=226.1 [M-H]-.
Embodiment 35
Following 5- diazanyl -6 of preparation structure, 7- epoxy ethyl baicaleins
6,7- epoxy ethyl baicaleins (296mg, 1mmol) is dissolved in 1-METHYLPYRROLIDONE (3mL), is added dropwise thereto Hydrazine hydrate (2.2mL, 45mmol), reacts 12 hours under nitrogen protective condition by 70 DEG C, is cooled to room temperature.Reactant liquor is poured into In 24mL frozen water, a large amount of dark yellow solids are separated out, crude product Jing Flash silica column chromatographies (eluant, eluent is dichloromethane: methyl alcohol=50: 1V/V) isolated product 5- diazanyl -6,7- epoxy ethyl baicaleins, yellow powder, its yield is 69%.The sign number of product According to：1H NMR (300MHz, CDCl3δppm)：7.64 (dd, J=8.2Hz, J=1.8Hz, 2H), 7.45 (m, 3H), 7.35 (s, 1H), 6.21 (s, 1H), 4.29 (m, 4H)；13C NMR (75MHz, CDCl3δppm)：173.2,150.4,149.2,143.2, 143.0,142.6,128.6,128.3,125.1,102.8,98.6,95.3,64.4,64.1；MS (ESI) m/z=309.1 [M- H]-。

Claims (10)

1. a kind of method for preparing aromatic amine compounds, it is characterised in that comprise the following steps：Under inert gas shielding, will Phenolic compound dissolves in a solvent in molar ratio with amine for 1: 2～40, and 50～140 DEG C are reacted 6～15 hours, is prepared into relative The aromatic amine compound answered, then the aromatic amine compound that post-treated acquisition is pure；Its reaction equation is as follows：
Wherein, phenolic compound is as shown in formula R OH, amine such as structural formulaIt is shown, aromatic amine compound such as structural formulaIt is shown；
Described phenolic compound ROH is selected from substituted or unsubstituted phenol, naphthols, pyridine, flavones, quinones；Wherein, The substituent of phenol is C1-7Alkyl, C1-4The C of alkoxyl, halogen substiuted1-7Alkyl, halogen, nitro, acetyl group or itrile group；
Described amineIn, R1For H, hydroxyl, amino, benzyl, O- benzyls, N, N- dimethyl ethyls, C5-6Cycloalkyl, C1-6 Alkyl,Substituted or unsubstituted phenyl；Wherein, m is the integer of 1-6, and n is 1-6 Integer；The substituent of described phenyl is C1-4Alkyl, C1-4The C of alkoxyl, halogen substiuted1-4Alkyl.
2. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that the substituent of phenol is C1-4 Alkyl, C1-3The C of alkoxyl, halogen substiuted1-4Alkyl, halogen, nitro, acetyl group or itrile group.
3. the method for preparing aromatic amine compounds according to claim 2, it is characterised in that the substituent of phenol is C1-2 Alkyl, C1-3The C that alkoxyl, F, Cl, Br replace1-2Alkyl, F, Cl, Br, nitro, acetyl group or itrile group.
4. the method for preparing aromatic amine compounds according to claim 1,2 or 3, it is characterised in that phenolic compound ROH can be selected from：Fortified phenol is p-nitrophenol, p-trifluoromethyl-phenol or 2- acetyl phenols；Naphthols be 1- naphthols or Beta naphthal；Flavone compound is 7- benzyl baicaleins, 6,7- dioxane baicaleins, 6,7- dibenzyl baicaleins, the wild root of large-flowered skullcap Element, 6,7- dioxane scutellarins, wogonin；Quinones is Isosorbide-5-Nitrae-DIANTHRAQUINONE or 1- naphthoquinones.
5. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that R1For H, hydroxyl, amino, benzyl Base, O- benzyls, N, N- dimethyl ethyls, C5-6Cycloalkyl, C1-4Alkyl,Replace or Unsubstituted phenyl；Wherein, m is the integer of 1-3, and n is the integer of 1-3；The substituent of described phenyl is C1-3Alkyl, C1-3Alkane The C that epoxide, F, Cl, Br replace1-4Alkyl.
6. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that described solvent be acetonitrile, Any one or its in DMF, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE, Isosorbide-5-Nitrae-dioxane or toluene Mixture.
7. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that described phenolic compound It is 1: 3～30 with the mol ratio of amine.
8. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that described phenolic compound Concentration be 0.1～10mol/L, preferably 0.3～5mol/L.
9. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that described reaction temperature is 50～150 DEG C, the reaction time is 3～24 hours.
10. the method for preparing aromatic amine compounds according to claim 1, it is characterised in that described post processing is： Reactant liquor is cooled to into room temperature, in pouring 3～15 times of water of reactant liquor into；If Precipitation, then suction filtration carries out silicon to filter cake again Glue post layer purifying obtains described aromatic amine product；If not there is Precipitation, it is added thereto to organic reagent and is extracted Take, organic phase is washed with saturated aqueous common salt, then with anhydrous sodium sulfate or magnesium sulfate drying, filtration, reduced pressure concentration, then carry out silicon Glue column chromatography obtains described aromatic amine product；Wherein, described organic reagent is ethyl acetate, ether, dichloromethane, just The one of which of butanol；It is dichloromethane: methyl alcohol=100: 1-30: 1V/V that the eluent of silica gel column chromatography is eluant, eluent.
CN201611194847.3A 2016-12-16 2016-12-16 Method for preparing aromatic amine compounds Pending CN106631820A (en)

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CN108043441A (en) * 2017-12-07 2018-05-18 苏州大学 Application of the ruthenium nano material of carbon load in catalysis aromatic amine and aromatic methanol reaction
CN115583884A (en) * 2022-11-23 2023-01-10 九江富达实业有限公司 Method for synthesizing 2, 4-dinitroaniline

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Publication number Priority date Publication date Assignee Title
CN108043441A (en) * 2017-12-07 2018-05-18 苏州大学 Application of the ruthenium nano material of carbon load in catalysis aromatic amine and aromatic methanol reaction
CN108043441B (en) * 2017-12-07 2021-09-28 苏州大学 Application of carbon-supported ruthenium nano material in catalyzing reaction of aromatic amine and aromatic methanol
CN115583884A (en) * 2022-11-23 2023-01-10 九江富达实业有限公司 Method for synthesizing 2, 4-dinitroaniline

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