CN109867691A - A kind of aryl amine derivant and its preparation method and application - Google Patents
A kind of aryl amine derivant and its preparation method and application Download PDFInfo
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- CN109867691A CN109867691A CN201910314759.XA CN201910314759A CN109867691A CN 109867691 A CN109867691 A CN 109867691A CN 201910314759 A CN201910314759 A CN 201910314759A CN 109867691 A CN109867691 A CN 109867691A
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- aryl
- hydrogen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 241001597008 Nomeidae Species 0.000 title abstract 6
- -1 heterocyclic radical Chemical class 0.000 claims abstract description 65
- 125000003118 aryl group Chemical group 0.000 claims abstract description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 125000000524 functional group Chemical group 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 10
- 125000004185 ester group Chemical group 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 24
- 229910052751 metal Inorganic materials 0.000 claims description 24
- 239000002184 metal Substances 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 16
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 16
- 235000001014 amino acid Nutrition 0.000 claims description 14
- 150000001413 amino acids Chemical class 0.000 claims description 13
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 9
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- 239000007800 oxidant agent Substances 0.000 claims description 8
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
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- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
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- 125000001041 indolyl group Chemical group 0.000 claims description 5
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
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- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
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- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
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- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 3
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- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
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- 150000004820 halides Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001174 sulfone group Chemical group 0.000 claims description 3
- 239000004474 valine Substances 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- ZECJHXWYQJXFQQ-UHFFFAOYSA-L CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Ir](Cl)Cl)C(C)=C1C ZECJHXWYQJXFQQ-UHFFFAOYSA-L 0.000 claims description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
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- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
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- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 2
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- CEXRSMNHLQGJRN-UHFFFAOYSA-N N-[[4-bromo-2-[2-tri(propan-2-yl)silylethynyl]phenyl]methyl]-1,1,1-trifluoromethanesulfonamide Chemical compound CC(C)[Si](C#CC1=C(C=CC(=C1)Br)CNS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C CEXRSMNHLQGJRN-UHFFFAOYSA-N 0.000 description 1
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005905 alkynylation reaction Methods 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000005264 aryl amine group Chemical group 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 238000007337 electrophilic addition reaction Methods 0.000 description 1
- KZGWPHUWNWRTEP-UHFFFAOYSA-N ethynyl-tri(propan-2-yl)silane Chemical group CC(C)[Si](C#C)(C(C)C)C(C)C KZGWPHUWNWRTEP-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 238000006464 oxidative addition reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000006247 phenyl propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to technical field of organic synthesis more particularly to a kind of aryl amine derivant and its preparation method and application.The present invention provides a kind of aryl amine derivant, shown in the structural formula such as formula (I) of the aryl amine derivant；Wherein, Ar is aryl, including fragrant heterocyclic radical, phenyl or aromatic condensed ring base；R1Selected from hydrogen, halogen element, ether or containing the alkyl of functional group；R2For hydrogen, alkyl or ester group；R3For polysubstituted silicon substrate；N is 1 or 2.Aryl amine derivant of the present invention is introduced with multi-functional alkynyl, and alkynyl is located at the ortho position of amido on aryl, in view of the chemical activity abundant of the triple carbon-carbon bonds of alkynyl, and extensive use of the arylamine in drug, aryl amine derivant of the present invention have a good application prospect in drug development.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an aryl amine derivative, and a preparation method and application thereof.
Background
The arylamine derivatives are widely present in drug molecules as important skeletons of molecules with biological activity, Ampicillin, a Pennislin analogue, Sensipar and Sertraline all have arylamine structures, and the Ampicillin and the Pennislin analogue have broad-spectrum antibacterial property; sensipar can be used to treat hormonal disorders; sertraline is used in the treatment of anti-depression with arylamines as its core skeleton. The aryl amine derivatives have important significance for developing new drug molecules. However, in the development of new drug molecules, there are problems that the kinds of arylamine derivatives are limited and the development of arylamine derivatives is still required to be broadened.
Therefore, how to broaden the variety of arylamine derivatives has been one of the focuses of extensive attention of researchers in the field.
Disclosure of Invention
In view of the above, the present invention provides an arylamine derivative, and a preparation method and an application thereof, which are used for providing a new arylamine derivative and widening the variety of the arylamine derivative.
The specific technical scheme of the invention is as follows:
an arylamine derivative has a structural formula shown in formula (I):
wherein Ar is aryl, including aromatic heterocyclic group, phenyl or aromatic condensed ring group; r1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r2Is hydrogen, alkyl or ester group; r3Is a polysubstituted silicon base; n is 1 or 2.
The aryl amine derivative introduces multifunctional alkynyl, and the alkynyl is positioned at the ortho position of the amino on the aryl, so the aryl amine derivative has good application prospect in the development of medicaments in view of rich chemical activity of carbon-carbon triple bond of the alkynyl and wide application of the aryl amine in medicaments.
The aryl amine derivative can be used for carrying out subsequent conversion conveniently by combining various conversion reactions of amino and alkynyl, including addition and condensation of amino, electrophilic addition of alkynyl, nucleophilic addition reaction, Click reaction and the like, and can carry out intramolecular cyclization reaction, namely carbon-hydrogen bond cyclization reaction on amino and benzene ring promoted by metal catalysis and strong oxidizer, and intramolecular nucleophilic addition reaction of amino to alkynyl can be carried out to obtain indoline and tetrahydroquinoline derivatives.
In the present invention, Ar is preferably a benzene ring. The aromatic heterocyclic group is N, O and/or S-containing heterocyclic group, and is preferably indolyl, furyl or thienyl; the aromatic condensed ring group is preferably naphthalene or anthracene; the alkyl containing functional group is saturated or unsaturated straight chain alkyl, branched chain alkyl or cyclic alkyl, and the cyclic alkyl comprises condensed ring group. Alkyl groups include methyl, ethyl, isopropyl or tert-butyl.
In the invention, n is 1 or 2, and the aryl amine derivative is aryl ethyl amine derivative or aryl propyl amine derivative.
In the present invention, R1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r1Can be in the ortho, meta or para position relative to the amine group. The halogen element is selected from chlorine (Cl), bromine (Br) or fluorine (F).
Preferably, the functional group in the functional group-containing hydrocarbon group is selected from a halogen element, an ester group, a carbonyl group, an amino group, a nitro group, a cyano group, a sulfone group or an acyl group;
the hydrocarbyl containing functional groups is substituted straight-chain hydrocarbyl or substituted cyclic hydrocarbyl.
Preferably, Ar is phenyl, naphthyl, thienyl or indolyl;
the R is3Is triisopropylsilyl (-TIPS), trimethylsilyl (-TMS) or dimethyl tert-butylsilyl (-TBS).
In the present invention, -NHTf is trifluoromethanesulfonylamino.
Preferably, the arylamine derivatives of formula (I) are selected from
The invention also provides a preparation method of the aryl amine derivative, which comprises the following steps:
reacting a compound shown in a formula (II) with a compound shown in a formula (III) to obtain an arylamine derivative shown in a formula (I);
wherein,ar is aryl, including aromatic heterocyclic radical, phenyl or aromatic condensed ring radical; r1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r2Is hydrogen, alkyl or ester group, n is 1 or 2;R3is a multi-substituted silicon base, X is hydrogen, bromine, iodine or an iodine-containing heterocyclic group, and iodine in the iodine-containing heterocyclic group is connected with a carbon-carbon triple bond;
preferably, the reaction of the compound shown in the formula (II) and the compound shown in the formula (III) is specifically as follows:
dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent, and reacting under the action of an amino acid ligand, an oxidant and a metal catalyst under an alkaline condition.
In the prior art, the efficient synthesis method of aryl amine derivatives is few, and usually involves multi-step reactions, including reductive amination of carbonyl derivatives and the like, so that a method for quickly constructing aryl amine functional molecules is urgently required. Although the carbon-carbon triple bond of alkynyl has multifunctionality, a method for introducing alkynyl segments at ortho position assisted by arylamine has not been developed, and currently, a Sonogashira coupling reaction is carried out on a substrate with halogen substituted at the ortho position of the aromatic ring of arylamine to obtain the arylamine derivative with ortho alkynyl. However, there are few types of arylamine derivatives having a halogen at the ortho position of the aromatic ring, and the conventional methods are difficult to synthesize.
In the preparation method, the reaction is a regioselective aryl carbon-hydrogen bond alkynylation reaction of arylamine compounds, under the action of a metal catalyst and a ligand and under the promotion of an oxidant, the aryl carbon-hydrogen bond of the aryl is directly subjected to the regioselective functionalization reaction by adopting the arylamine compounds which are simple, easy to obtain and widely available, and the alkynyl with the versatility is introduced into the molecule, so that the arylamine derivative containing the alkynyl and having the potential bioactivity is obtained. The preparation method has the advantages of simple and easily-obtained substrate, few reaction steps and simple operation, can be synthesized by a one-pot method, and can realize the high-efficiency synthesis of various polysubstituted arylamine derivatives; the reaction only occurs at the ortho position of the aryl of the compound shown in the formula (II), and the regioselectivity is good; the carbon-hydrogen bond in the reaction is superior to the carbon-halogen bond, the chemical selectivity is good, and the development requirement of sustainable chemistry is met.
The preparation method has wide application range of the substrate, the obtained aryl amine derivative is easy to convert subsequently, and the preparation method has good atom economy. In addition, the preparation method can directly carry out later modification on the amine derivatives with potential biological activity.
The preparation method has good area selectivity, wide substrate range and atom economy, and the aryl amine derivative has good application value in the fields of biology and materials. The invention also provides a new strategy for the transformation of compounds with good biological and pharmaceutical activities, such as amino acid, amino alcohol and the like.
Preferably, the metal in the metal catalyst is selected from one or more of palladium, iridium and rhodium, preferably from palladium acetate (Pd (OAc)2) Palladium chloride (PdCl)2) Palladium dichlorodiacetonitrile (PdCl)2(MeCN)2) Palladium trifluoromethanesulfonate (Pd (OTf)2) Pentamethylcyclopentadienyliridium chloride dimer ([ Cp & RhCl)2]2) And a trisacetonitrile-pentamethylcyclopentadienylrhodium hexafluorotellurate dimer ([ CpRh (MeCN))3][SbF6]2) One or more of (a).
In the present invention, the metal catalyst is preferably a divalent palladium metal catalyst, and more preferably palladium acetate.
In the preparation method, a compound shown in a formula (II) is adopted, the compound shown in the formula (II) is an aryl ethylamine or aryl propylamine compound, a nitrogen atom of the compound shown in the formula (II) is replaced by trifluoromethanesulfonyl, and the trifluoromethanesulfonyl can be used as a strong electron-withdrawing group to accelerate the leaving of hydrogen on the nitrogen atom, so that the coordination of a divalent palladium salt catalyst and the nitrogen atom is accelerated; meanwhile, the trifluoromethanesulfonyl can be used as a weak coordination group to coordinate with a metal catalyst, namely a divalent palladium salt, so as to promote the generation of a relatively more stable intermediate, namely a relatively stable six-membered or seven-membered cyclic metal intermediate; the use of the amino acid ligand not only stabilizes the cyclic metal intermediate, but also serves as intramolecular proton transfer to assist the breakage of hydrocarbon bonds; whereas sigma donor ligands can enhance oxidative addition type carbon-hydrogen bond activation by increasing the electron abundance of the low-valent metal center. According to the invention, through good selection of a substrate and an amino acid ligand, an important basis is provided for realizing ortho-position regioselectivity and remote-oriented reaction activity of aryl ethylamine and aryl propylamine derivative-oriented aromatic ring carbon-hydrogen bonding ethynylation reaction.
Compared with the common regioselective carbon-hydrogen bond functionalization reaction realized by the metal five-membered ring intermediate, the reaction realizes the more remote carbon-hydrogen bond functionalization reaction through the six-membered ring or seven-membered ring organometallic intermediate, and provides a new idea for the remote selective carbon-hydrogen bond functionalization reaction.
In the present invention, Ar is preferably a benzene ring. The aromatic heterocyclic group is N, O and/or S-containing heterocyclic group, and is preferably indolyl, furyl or thienyl; the aromatic condensed ring group is preferably naphthalene or anthracene. The alkyl containing functional group is saturated or unsaturated straight chain alkyl, branched chain alkyl or cyclic alkyl, and the cyclic alkyl comprises condensed ring group. Alkyl groups include methyl, ethyl, isopropyl or tert-butyl.
In the invention, n is 1 or 2, and the aryl amine derivative is aryl ethyl amine derivative or aryl propyl amine derivative.
In the present invention, R1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r1Can be in the ortho, meta or para position relative to the amine group. The halogen element is selected from chlorine (Cl), bromine (Br) or fluorine (F).
Preferably, the functional group in the functional group-containing hydrocarbon group is selected from a halogen element, an ester group, a carbonyl group, an amino group, a nitro group, a cyano group, a sulfone group or an acyl group;
the hydrocarbyl containing functional groups is substituted straight-chain hydrocarbyl or substituted cyclic hydrocarbyl.
Preferably, Ar is phenyl, naphthyl, furyl, indolyl or thienyl;
the R is3Is triisopropylsilyl (-TIPS), trimethylsilyl (-TMS) or dimethyl tert-butylsilyl (-TBS).
In the present invention, -NHTf is trifluoromethanesulfonylamino.
Preferably, the arylamine derivatives of formula (I) are selected from
The compound of the formula (III) is preferably(1- ((triisopropylsilyl) -1. lambda.3-phenyl [ d ]][1,2]Iodoxy-3 (1H) -one), the compound of formula (III) can be pre-synthesized or commercially available.
The compound of formula (II) is preferably The compound shown in the formula (II) can be obtained by one-step high-efficiency synthesis through condensation reaction of commercially available amine and trifluoromethanesulfonic anhydride.
Preferably, the amino acid ligand is selected from amino acids substituted by acyl on nitrogen atom, the amino acid is one or more of leucine, phenylalanine, glutamic acid, glycine and valine, more preferably, the amino acid ligand is leucine, phenylalanine, glutamic acid, glycine and valine substituted by acetyl or tert-butyloxycarbonyl, and more preferably, N-tert-butyloxycarbonyl-leucine.
Preferably, the oxidant is selected from silver acetate (AgOAc), silver carbonate (Ag)2CO3) Silver triflate, silver nitrate, copper acetate, cuprous halide, copper halide, iron trihalideAnd ferric nitrate, more preferably silver acetate;
the alkali for adjusting alkaline condition is selected from sodium acetate, and cesium acetate (CH)3COOCs), potassium acetate, sodium carbonate or potassium phosphate, more preferably sodium acetate.
In the invention, the reaction temperature is 80-120 ℃, and more preferably 100 ℃;
the reaction time is 12-24 h.
In the present invention, the inert solvent is selected from toluene, tetrahydrofuran, 1, 4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol or water, and more preferably 1, 2-dichloroethane.
The molar ratio of the compound represented by the formula (II) to the compound represented by the formula (III) is 1:1 to 1:3, and more preferably 1: 1.5;
the amount of the metal catalyst is 1 mol% to 5 mol%, more preferably 2 mol%, based on the amount of the compound represented by the formula (II).
In the invention, the dosage of the amino acid ligand is 3-50 mol%, more preferably 5 mol% of the dosage of the compound shown in the formula (II);
the amount of the alkali for adjusting the alkaline condition is 5 mol% to 50 mol%, more preferably 15 mol% of the amount of the compound represented by the formula (II);
the amount of the oxidizing agent is 10 to 300 mol%, more preferably 30 mol%, based on the amount of the compound represented by the formula (II).
The concentration of the compound represented by the formula (II) in the inert solvent is 0.1mol/L to 3.0mol/L, preferably 0.2 mol/L.
In the present invention, the preparation method preferably comprises the steps of: under the air atmosphere, sequentially adding 0.20mmol of a compound shown as a formula (II), 0.9mg of palladium acetate, 2.3mg of N-tert-butoxycarbonyl-leucine, 2.5mg of sodium acetate and 10.0mg of silver acetate into a reactor, injecting a 1, 2-dichloroethane (1mL) solution containing 18 mu L of triisopropylsilyl acetylene bromide (0.30mmol) into the reactor by using an injector, placing the reactor on a reaction device, adjusting the temperature to 100 ℃, carrying out reaction for 12h, determining the end of the reaction by thin-layer chromatography analysis, carrying out suction filtration on reaction liquid by using kieselguhr, carrying out rotary evaporation and concentration on the reaction liquid to obtain a crude product, and carrying out column chromatography on the crude product by using 400-mesh silica gel to separate the reaction product, wherein a developing agent is a solvent with a volume ratio of 50: 1-5: 1 with ethyl acetate to obtain the aryl amine derivative.
The invention also provides the application of the aryl amine derivative in the technical scheme and/or the aryl amine derivative prepared by the preparation method in the technical scheme in the preparation of medicaments.
The aryl amine derivative is convenient for subsequent conversion, can perform intramolecular cyclization reaction, namely performs cyclization reaction of amino and carbon-hydrogen bond on a benzene ring promoted by metal catalysis and a strong oxidant, and can also perform intramolecular nucleophilic addition reaction of amino to alkynyl to construct a polysubstituted quinoline heterocyclic compound, and the aryl amine derivative can be compatible with halogen such as fluorine, bromine and chlorine, can be compatible with coordination ether functional groups, and has good application prospect in medicine preparation.
In summary, the invention provides an arylamine derivative, wherein the structural formula of the arylamine derivative is shown as the formula (I); wherein Ar is aryl, including aromatic heterocyclic group, phenyl or aromatic condensed ring group; r1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r2Is hydrogen, alkyl or ester group; r3Is a polysubstituted silicon base; n is 1 or 2. The aryl amine derivative introduces multifunctional alkynyl, and the alkynyl is positioned at the ortho position of the amino on the aryl, so the aryl amine derivative has good application prospect in the development of medicaments in view of rich chemical activity of carbon-carbon triple bond of the alkynyl and wide application of the aryl amine in medicaments.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the NMR of N- (2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 1 of the present invention1H, spectrogram;
FIG. 2 shows the NMR of N- (2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 1 of the present invention13C, spectrum;
FIG. 3 shows NMR of N- (2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 1 of the present invention19F, spectrum;
FIG. 4 shows NMR of N- (4-chloro-2- ((isopropylsilyl) ethynyl) phenyl) -trifluoromethanesulfonamide provided in example 2 of the present invention1H, spectrogram;
FIG. 5 shows NMR of N- (4-chloro-2- ((isopropylsilyl) ethynyl) phenyl) -trifluoromethanesulfonamide provided in example 2 of the present invention13C, spectrum;
FIG. 6 shows NMR of N- (4-chloro-2- ((isopropylsilyl) ethynyl) phenyl) -trifluoromethanesulfonamide provided in example 2 of the present invention19F, spectrum;
FIG. 7 shows the NMR of N- (3-fluoro-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 3 of the present invention1H, spectrogram;
FIG. 8 shows NMR of N- (3-fluoro-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 3 of the present invention13C, spectrum;
FIG. 9 shows NMR of N- (3-fluoro-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 3 of the present invention19F, spectrum;
FIG. 10 shows an embodiment of the present inventionNuclear magnetic resonance of N- (3-methoxy-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 41H, spectrogram;
FIG. 11 shows the NMR of N- (3-methoxy-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 4 of the present invention13C, spectrum;
FIG. 12 shows the NMR of N- (3-methoxy-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide provided in example 4 of the present invention19F, spectrum;
FIG. 13 shows NMR of N- (2- (3- ((isopropylsilyl) ethynyl) thiophen-2-yl) ethyl) trifluoromethanesulfonamide provided in example 5 of the present invention1H, spectrogram;
FIG. 14 shows NMR of N- (2- (3- ((isopropylsilyl) ethynyl) thiophen-2-yl) ethyl) trifluoromethanesulfonamide provided in example 5 of the present invention13C, spectrum;
FIG. 15 shows NMR of N- (2- (3- ((isopropylsilyl) ethynyl) thiophen-2-yl) ethyl) trifluoromethanesulfonamide provided in example 5 of the present invention19F, spectrum;
FIG. 16 shows NMR spectra of methyl (S) -2- ((trifluoromethanesulfonamido) -4- (2- ((triisopropylsilyl) phenylbutyrate provided in example 6 of the present invention1H, spectrogram;
FIG. 17 shows NMR spectra of methyl (S) -2- ((trifluoromethanesulfonamido) -4- (2- ((triisopropylsilyl) phenylbutyrate provided in example 6 of the present invention13C, spectrum;
FIG. 18 shows NMR spectra of methyl (S) -2- ((trifluoromethanesulfonamido) -4- (2- ((triisopropylsilyl) phenylbutyrate provided in example 6 of the present invention19And F, spectrum.
Detailed Description
The invention provides an aryl amine derivative, a preparation method and application thereof, which are used for providing a new aryl amine derivative and widening the variety of the aryl amine derivative.
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
This example carries out the preparation of N- (2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3a), which has the following reaction scheme:
to a 15mL Schlenk reaction tube, a phenethylamine compound 1a (50.6mg,0.20mmol), a palladium (II) metal catalyst Pd (OAc) were added in this order under an atmospheric pressure air atmosphere2(0.9mg,0.004mmol), N-t-butoxycarbonyl-leucine (2.3mg,0.01mmol), sodium acetate (2.5mg,0.03mmol), silver acetate (10.0mg,0.06mmol), and finally injecting a 1, 2-dichloroethane (DCE,1mL) solution of the alkynyl bromide compound 2a (18. mu.L, 0.30mmol) into a reactor by a syringe, reacting at 100 ℃ for 12h, cooling to room temperature after the reaction is finished, filtering with celite, and concentrating by using a rotary evaporator to obtain a crude product. And (3) performing column chromatography separation on the crude product by adopting 400-mesh silica gel, wherein the volume ratio of the selected developing agent or eluent is 10: 1 with ethyl acetate to give the product N- (2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3a) in 75.3mg, yield 87% and purity 95%.
Nmr measurements were performed on N- (2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3a), with reference to figures 1-3, with the results:1H NMR(400MHz,CDCl3):δ7.53-7.51(m,1H),7.30(dt,J＝1.6Hz,7.6Hz,2H),7.25(dd,J＝0.8Hz,1H),7.22-7.20(m,1H),4.88(brs,1H),3.65(dd,J＝6.4Hz,12.4Hz,2H),3.11(t,J＝6.4Hz,2H),1.15-1.05(m,21H)；13C NMR(100MHz,CDCl3):δ138.75,133.5,129.5,129.0,127.2,123.3,104.9,95.8,44.6,35.2,18.6,11.3；19F NMR(100MHz,CDCl3):δ-77.43.
phenethylamine derivatives such as dopamine play an important role in drugs for treating nervous systems, and the reaction in the embodiment greatly widens the type of amine substrates realized by carbon-hydrogen bond activation in the prior art, and provides new raw materials for the development of new drug molecules.
Example 2
This example carries out the preparation of N- (4-chloro-2- ((isopropylsilyl) ethynyl) phenyl) -trifluoromethanesulfonamide (3b), which has the following reaction scheme:
to a 15mL Schlenk reaction tube, a phenethylamine compound 1b (57.4mg,0.20mmol), a palladium (II) metal catalyst Pd (OAc) were added in this order under an atmospheric pressure air atmosphere2(0.9mg,0.004mmol), N-t-butoxycarbonyl-leucine (2.3mg,0.01mmol), sodium acetate (2.5mg,0.03mmol), silver acetate (10.0mg,0.06mmol), and finally a solution of the alkynyl bromide compound 2a (18. mu.L, 0.30mmol) in 1, 2-dichloroethane (DCE,1mL) was injected into the reactor with a syringe and reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating by using a rotary evaporator to obtain a crude product. And (3) performing column chromatography separation on the crude product by adopting 400-mesh silica gel, wherein the volume ratio of the selected developing agent or eluent is 10: 1 with ethyl acetate to give the product N- (4-chloro-2- ((isopropylsilyl) ethynyl) phenyl) -trifluoromethanesulfonamide (3b) in 77.5mg, 83% yield and 95% purity.
Nmr examination of N- (4-chloro-2- ((isopropylsilyl) ethynyl) phenyl) -trifluoromethanesulfonamide (3b), see fig. 4-6, results are:1H NMR(400MHz,CDCl3):δ7.49(d,J＝2.0Hz,1H),7.28(dd,J＝2.4Hz,8.4Hz,1H),7.15(d,J＝8.0Hz,1H),4.84(brs,1H),3.62(t,J＝6.4Hz,2H),3.08(t,J＝6.8Hz,2H),1.135-1.127(m,21H)；13C NMR(100MHz,CDCl3):δ137.2,133.0,130.8,129.1,124.9,118.0,103.4,97.5,44.4,34.8,18.6,11.2；19F NMR(100MHz,CDCl3):δ-77.39。
this example shows that the preparation method of the present invention can combine an aryl carbon-halogen bond that is easily convertible, thereby providing a complementary method for coupling reaction with a Sonogashira-type carbon-halogen bond and an alkyne.
Example 3
This example carries out the preparation of N- (3-fluoro-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3c), which has the following reaction scheme:
to a 15mL Schlenk reaction tube, a phenethylamine compound 1c (54.2mg,0.20mmol), a palladium (II) metal catalyst Pd (OAc) were added in this order under an atmospheric pressure air atmosphere2(0.9mg,0.004mmol), N-t-butoxycarbonyl-leucine (2.3mg,0.01mmol), sodium acetate (2.5mg,0.03mmol), silver acetate (10.0mg,0.06mmol), and finally mixing the alkynyl-containing compound 2b (1- ((triisopropylsilyl) -1. lambda3-phenyl [ d ]][1,2]A solution of iodoxy-3 (1H) -one) (167mg,0.30mmol) in 1, 2-dichloroethane (DCE,1mL) was injected into the reactor with a syringe and reacted at 100 ℃ for 12H. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating by using a rotary evaporator to obtain a crude product. And (3) performing column chromatography separation on the crude product by adopting 400-mesh silica gel, wherein the volume ratio of the selected developing agent or eluent is 10: 1 petroleum ether and ethyl acetate to obtainTo the product, N- (3-fluoro-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3c), 68.5mg, yield 76%, purity 95%.
Nmr examination of N- (3-fluoro-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3c) is shown in fig. 7-9, with the results:1H NMR(400MHz,CDCl3):δ7.52-7.48(m,1H),6.97-6.93(m,2H),7.31(s,1H),4.96(brs,1H),3.64(d,J＝4.0Hz,2H),3.10(t,J＝6.4Hz,2H),1.13-1.10(m,21H)；13C NMR(100MHz,CDCl3):δ161.2,141.4,135.3,135.2,119.4,116.8,116.5,114.7,103.8,95.6,44.4,35.2,18.6,11.2；19F NMR(100MHz,CDCl3):δ-77.45,-109.43。
the embodiment shows that the preparation method of the invention can be compatible with fluorine widely existing in the fields of materials and biological medicines, and provides a basis for the wide application of the fluorine; and shows that the reaction area of the preparation method of the invention selectively proceeds in the aryl carbon-hydrogen bond with smaller resistance.
Example 4
This example carries out the preparation of N- (3-methoxy-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3d), which has the following reaction scheme:
a15 mL Schlenk reaction tube was sequentially charged with phenethylamine compound 1d (56.6mg,0.20mmol) and higher iodine alkynyl compound 2b (1- ((triisopropylsilyl) -1. lambda. in an atmospheric air atmosphere3-phenyl [ d ]][1,2]Iodoxy-3 (1H) -one) (167mg,0.30mmol), Palladium II Metal catalyst Pd (OAc)2(0.9mg,0.004mmol), N-t-butoxycarbonyl-leucine (2.3mg,0.01mmol), sodium acetate (2.5mg,0.03mmol), silver acetate (10mg,0.06mmol) and 1, 2-dichloroethane (DCE,1mL) were reacted at 100 ℃ for 12 hours. Cooling to room temperature after the reaction is finished, and passing through siliconAfter the filtration of the diatomaceous earth, the crude product was obtained by concentration using a rotary evaporator. And (3) performing column chromatography separation on the crude product by adopting 400-mesh silica gel, wherein the volume ratio of the selected developing agent or eluent is 10: 1 with ethyl acetate to give the product N- (4-bromo-2- ((triisopropylsilyl) ethynyl) benzyl) trifluoromethanesulfonamide (3d), 71.3mg, 77% yield and 95% purity.
Nmr examination of N- (3-methoxy-2- ((triisopropylsilyl) ethynyl) phenethyl) trifluoromethanesulfonamide (3d), see fig. 10-12, results are:1H NMR(400MHz,CDCl3):δ7.45(d,J＝8.4Hz,1H),6.82-6.77(m,1H),6.76-6.73(m,1H),4.96(brs,1H),3.81(s,3H),3.65(t,J＝6.4Hz,2H),3.08(t,J＝6.4Hz,2H),1.15-1.13(m,21H).13C NMR(100MHz,CDCl3):δ159.9,140.6,134.9,115.4,115.3,112.8,105.0,93.9,55.4,44.5,35.4,18.7,11.3.19F NMR(100MHz,CDCl3):δ-77.44.
the embodiment shows that the preparation method is sensitive to steric hindrance and can carry out reaction on aryl carbon-hydrogen bonds with smaller steric hindrance regioselectively.
Example 5
This example carries out the preparation of N- (2- (3- ((isopropylsilyl) ethynyl) thiophen-2-yl) ethyl) trifluoromethanesulfonamide (3e), which has the following reaction scheme:
to a 15mL Schlenk reaction tube, in an atmospheric air atmosphere, were added in the order of thiophenylamine-based compound 1e (51.8mg,0.20mmol), palladium (II) metal catalyst Pd (OAc)2(0.9mg,0.004mmol), N-t-butoxycarbonyl-leucine (2.3mg,0.01mmol), sodium acetate (2.5mg,0.03mmol), silver acetate (10.0mg,0.06mmol), and finally a solution of the alkynyl bromide compound 2a (18. mu.L, 0.30mmol) in 1, 2-dichloroethane (DCE,1mL) was injected into the reactor with a syringe at a temperature of 1.3. mu.LReacting at 80 ℃ for 6h, cooling to room temperature after the reaction is finished, performing suction filtration on the product through diatomite, and concentrating the product by using a rotary evaporator to obtain a crude product. And (3) performing column chromatography separation on the crude product by adopting 400-mesh silica gel, wherein the volume ratio of the selected developing agent or eluent is 10: 1 with ethyl acetate to give the product N- (2- (3- ((isopropylsilyl) ethynyl) thiophen-2-yl) ethyl) trifluoromethanesulfonamide (3e) 77.3mg, 88% yield and 95% purity.
Nmr measurements were made on N- (2- (3- ((isopropylsilyl) ethynyl) thiophen-2-yl) ethyl) trifluoromethanesulfonamide (3e), see figures 13-15, with the results:1H NMR(400MHz,CDCl3)：δ7.12(d,J＝5.2Hz,1H),7.05(d,J＝5.2Hz,1H),4.98(brs,1H),3.64(dd,J＝6.0Hz,12.0Hz,2H),3.23(t,J＝6.8Hz,2H),1.125-1.120(m,21H)；13C NMR(100MHz,CDCl3)：δ142.2,130.6,123.5,121.8,100.4,94.6,44.8,29.7,18.6,11.2；19F NMR(100MHz,CDCl3):δ-77.40。
the embodiment shows that the preparation method is compatible with thiophene derivatives widely applied in material medicine, and the multifunctional thiophene-based fused ring compound can be conveniently and quickly obtained by combining the amine palladation reaction of intramolecular alkyne catalyzed by metal.
Example 6
This example carries out the preparation of methyl (S) -2- ((trifluoromethanesulfonamido) -4- (2- ((triisopropylsilyl) phenylbutyrate (3f), having the formula:
to a 15mL Schlenk reaction tube, a phenethylamine compound 1f (65.0mg,0.20mmol), a palladium (II) metal catalyst Pd (OAc) were added in this order under an atmospheric pressure air atmosphere2(0.9mg,0.004mmol), N-t-butoxycarbonyl-leucine (2.3mg,0.01mmol), sodium acetate (2.5mg,0.03mmol), and vinegarSilver acid (10.0mg,0.06mmol), potassium carbonate (5.52mg,0.04mmol), finally, a solution of alkynylbromide 2a (18 μ L,0.30mmol) in 1, 2-dichloroethane (DCE,1mL) was injected into the reactor with a syringe, reacted at 100 ℃ for 12h, cooled to room temperature after the reaction was completed, suction filtered through celite, and concentrated using a rotary evaporator to give the crude product. And (3) performing column chromatography separation on the crude product by adopting 400-mesh silica gel, wherein the volume ratio of the selected developing agent or eluent is 10: 1 with ethyl acetate to give the product (S) -methyl 2- (trifluoromethanesulfonamido) -4- (2- ((triisopropylsilyl) phenylbutyrate (3f), 80.8mg, 80% yield and 95% purity.
Nmr detection of (S) -methyl 2- (trifluoromethanesulfonamido) -4- (2- ((triisopropylsilyl) phenylbutyrate (3f) is shown in fig. 16-18, with the results:1H NMR(400MHz,CDCl3):δ7.48(d,J＝7.6Hz,1H),7.19(d,J＝7.6Hz,2H),5.51(brs,1H),4.23-4.19(m,2H),4.17-4.12(m,1H),3.00-2.93(m,2H),2.35-2.26(m,1H),2.11-2.02(m,1H),1.26(t,J＝7.2Hz,3H),1.14(s,21H)；13C NMR(100MHz,CDCl3):δ170.7,141.8,133.4,128.9,128.7,126.5,123.1,100.0,95.1,62.4,57.1,33.9,30.5,18.7,14.0,11.3；19F NMR(100MHz,CDCl3):δ-77.51,-77.52。
the embodiment shows that the preparation method of the invention is compatible with the phenylpropyl amino acid derivatives widely applied in material medicine, and the embodiment shows that the preparation method of the invention can realize the selective functionalization reaction of the far-end carbon-hydrogen bond through the seven-element organic metal cyclic intermediate.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. An arylamine derivative is characterized in that the structural formula of the arylamine derivative is shown as a formula (I):
wherein Ar is aryl, including aromatic heterocyclic group, phenyl or aromatic condensed ring group; r1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r2Is hydrogen, alkyl or ester group; r3To polysubstituted siliconA group; n is 1 or 2.
2. Arylamine derivatives according to claim 1, characterized in that the functional group in the functional group-containing hydrocarbon group is selected from halogen elements, ester groups, carbonyl groups, amino groups, nitro groups, cyano groups, sulfone groups or acyl groups;
the hydrocarbyl containing functional groups is substituted straight-chain hydrocarbyl or substituted cyclic hydrocarbyl.
3. Arylamine derivatives according to claim 1, characterized in that Ar is phenyl, naphthyl, thienyl or indolyl;
the R is3Is triisopropyl silicon base, trimethyl silicon base or dimethyl tertiary butyl silicon base.
4. Arylamine derivatives according to claim 1, characterized in that the arylamine derivatives of formula (I) are selected from
5. A preparation method of aryl amine derivatives is characterized by comprising the following steps:
reacting a compound shown in a formula (II) with a compound shown in a formula (III) to obtain an arylamine derivative shown in a formula (I);
wherein,ar is aryl, including aromatic heterocyclic radical, phenyl or aromatic condensed ring radical; r1Selected from hydrogen, halogen elements, ether groups or hydrocarbon groups containing functional groups; r2Is hydrogen, alkyl or ester group, n is 1 or 2;R3is polysubstituted silicon base, X is hydrogen, bromine, iodine or iodineA heterocyclic group having iodine attached to a carbon-carbon triple bond;
6. the method according to claim 5, wherein the reaction of the compound of formula (II) with the compound of formula (III) is carried out by:
dissolving a compound shown in a formula (II) and a compound shown in a formula (III) in an inert solvent, and reacting under the action of an amino acid ligand, an oxidant and a metal catalyst under an alkaline condition.
7. The process according to claim 6, wherein the metal in the metal catalyst is selected from one or more of palladium, iridium and rhodium, preferably from one or more of palladium acetate, palladium chloride, dichlorodiacetonitrile palladium, palladium trifluoromethanesulfonate, pentamethylcyclopentadienyliridium chloride dimer and trisacetonitrile-pentamethylcyclopentadienylrhodium chloride dimer.
8. The method according to claim 7, wherein the amino acid ligand is selected from the group consisting of an amino acid substituted with an acyl group on a nitrogen atom, and the amino acid is one or more of leucine, phenylalanine, glutamic acid, glycine and valine.
9. The method according to claim 6, wherein the oxidizing agent is selected from one or more of silver acetate, silver carbonate, silver triflate, silver nitrate, copper acetate, cuprous halide, cupric halide, ferric trihalide, and ferric nitrate;
the alkali for adjusting the alkaline condition is selected from sodium acetate, cesium acetate, potassium acetate, sodium carbonate or potassium phosphate.
10. Use of arylamine derivatives according to any one of claims 1 to 4 and/or of arylamine derivatives obtained by the process according to any one of claims 5 to 9 for the preparation of medicaments.
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