CN107973742A - The method for preparing 3- indole ketone compounds - Google Patents
The method for preparing 3- indole ketone compounds Download PDFInfo
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- CN107973742A CN107973742A CN201610921842.XA CN201610921842A CN107973742A CN 107973742 A CN107973742 A CN 107973742A CN 201610921842 A CN201610921842 A CN 201610921842A CN 107973742 A CN107973742 A CN 107973742A
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- 0 *C1(C(N*)=O)N(C(*)=O)c(cccc2)c2C1=O Chemical compound *C1(C(N*)=O)N(C(*)=O)c(cccc2)c2C1=O 0.000 description 1
- MTODGLDLTLLCTC-UHFFFAOYSA-N COc1ccc(C2(C(NCCc3ccccc3)=O)N(C(c3ccccc3)=O)c(cccc3)c3C2=O)cc1 Chemical compound COc1ccc(C2(C(NCCc3ccccc3)=O)N(C(c3ccccc3)=O)c(cccc3)c3C2=O)cc1 MTODGLDLTLLCTC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
This application provides the method for preparing 3 indole ketone compounds and 3 indole ketone compounds obtained by this method.
Description
Technical field
The 3- indole ketone chemical combination obtained this application involves the method for preparing 3- indole ketone compounds and by this method
Thing.
Background technology
3- indole ketone compounds are important medicine intermediate, while it also has very high bioactivity, can press down
Cyclooxygenase (COX) in human body processed, so as to play the role of anti-inflammatory.In addition, the compound that part has similar structures may be used also
Hectic fever illness during for Woman climacteric, reduces hot flush.It has further been found that such compound also has
Liver cancer cells are particularly had preferable inhibition by preferable antitumor activity.
The reactions steps that the prior synthesizing method of 3- indole ketone derivatives includes are more, for example, intramolecular nitroparaffins
Redox-Dipolar cyclisation cascade reaction.But this kind of reaction uses golden metal catalytic, and raw material needs to synthesize, therefore
The overwhelming majority is not carried out being commercialized.Org.Lett.2015, discloses using lawrencium metal as catalyst in 17,270-273,1H-
Pyrroles -2,5- diketone derivative synthesizes 3- indole ketone derivatives for raw material.This synthetic method it is similarly subjected to raw material
Limitation, most raw materials still need to synthesize.(Chem.Eur.J.2014,20,3283-3288)
Summary
This application involves the method for preparing the 3- indole ketone compounds represented by formula (I), it includes that aldehydes will be included
Compound, 2- aminobenzoic acid esters compounds or 2- aminophenyl acetic acids ester type compound, carboxylic acid compound and isocyanide class chemical combination
The mixture of thing adds solvent, and the mixture for adding the solvent is heated；
Wherein, R1、R2、R3And R4It is each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, fragrant alkene
Base, aryloxy group, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl；
The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, arylalkenyl, aryloxy group, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical,
Cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl are optionally substituted selected from following group：Alkyl, halogen,
Nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
In presently filed embodiment, the described method includes：
Aldehyde compound, 2- aminobenzoic acid esters compounds or 2- aminophenyl acetic acids ester type compound, carboxylic acid will be included
The mixture of class compound and different cyanides adds the first solvent；
Optionally, the mixture for adding the first solvent is stirred at normal temperatures；
By the first solvent concentration in mixture or removal；And
It will remove or the mixture of the first solvent of concentration adds the second solvent and the mixture to adding the second solvent heats；
Wherein described first solvent and second solvent are identical or different.
The application further relates to the 3- indole ketone compounds obtained by the present processes.
In some embodiments, present document relates to 3- indole ketone derivatives synthesis using one pot of multi-component reaction
Method, reactant is reacted in certain proportion, and by shirtsleeve operation, target product is obtained after step purification.
In some embodiments, method disclosed herein operates change that is relatively simple, and passing through raw material mix
The compound of similar structures can be synthesized.
It is described in detail
Definition
As used in the specification and the appended claims, unless there are opposite certain illustrated, following term tool
There is the meaning being expressed as below.
" aldehyde compound " refers to the compound containing "-CHO " functional group.
" carboxylic acid compound " refers to containing " the compound of-C (O) OH " functional groups.
" different cyanides " refers to containing "-N+≡C-" functional group compound.
" alkyl " refers to the straight or branched hydrocarbon chain radical for the saturation being only made of carbon atom and hydrogen atom, it has 1
To 12 carbon atoms (for example, there is 1,2,3,4,5,6,7,8,9,10,11,12 carbon atom), preferably 1 to 8 carbon atom, more
It is preferred that 1 to 6 carbon atom, and connected by the remainder of singly-bound and molecule, such as, methyl, ethyl, n-propyl, 1- first
Base ethyl (isopropyl), normal-butyl, n-pentyl, 1,1- dimethyl ethyls (tert-butyl group), 3- methylhexyls, 2- methylhexyls etc..
Alkyl can optionally be substituted by following groups：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon
Base, heterocyclic radical and heteroaryl.
" alkenyl " refer to the straight or branched hydrocarbon chain comprising at least one double bond that is only made of carbon atom and hydrogen atom from
By base, it is with 2 to 12 carbon atoms (for example, with 2,3,4,5,6,7,8,9,10,11,12 carbon atoms), and preferably 1 to 8
A carbon atom and its by the remainder of singly-bound and molecule connect, for example, vinyl, propyl- 1- alkenyls, but-1-ene base,
Amyl- 1- alkenyls, amyl- Isosorbide-5-Nitrae-dialkylene etc..Alkenyl can optionally be substituted by following groups：Alkyl, halogen, nitro, acyl group, acyl
Amino, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" alkynyl " refer to the straight or branched hydrocarbon chain comprising at least one three key that is only made of carbon atom and hydrogen atom from
By base, it is with 2 to 12 carbon atoms (for example, with 2,3,4,5,6,7,8,9,10,11,12 carbon atoms), and preferably 1 to 8
A carbon atom and its by the remainder of singly-bound and molecule connect, for example, Propargyl, butyl- 2- alkynyls, amyl- 3- alkynyls
Deng.Alkynyl can optionally be substituted by following groups：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, ring
Alkyl, heterocyclic radical and heteroaryl.
" alkoxy " refers to formula-ORaFree radical, wherein RaFor comprising 1 to 12 carbon atom (for example, with 1,2,3,4,
5th, 6,7,8,9,10,11,12 carbon atoms) alkyl as defined above.The moieties of alkoxy can be appointed by following groups
Selection of land substitutes：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" aryl " refers to comprising hydrogen, 6 to 18 carbon atoms (6,7,8,9,10,11,12,13,14,15,16,17 or 18
Carbon atom) and at least one aromatic ring hydrocarbon ring system free radical.For purposes of the present invention, aryl can be it is monocyclic, bicyclic, three
Ring or Fourth Ring loop system, it can include condensing or bridge joint loop system.Aryl include but not limited to benzo acenaphthene, acenaphthylene, vinegar phenanthrene alkene,
Anthracene, Azulene, benzene,, fluoranthene, fluorenes, asymmetric indacene, s-indacene, indane, indenes, naphthalene, that non-alkene, phenanthrene, seven days of the week alkene, pyrene and
Benzophenanthrene.Aryl can optionally be substituted by following groups：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, virtue
Base, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" aralkyl " refers to formula-Rb-RcFree radical, wherein RbFor alkylidene chain and RcAs above determine to be one or more
The aryl of justice, for example, benzyl, benzhydryl etc..The alkylidene chain part of aralkyl and aryl moiety can independently by selected from
Under group optionally substitute：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and
Heteroaryl.
" arylalkenyl " refers to formula-RdRcFree radical, wherein RdFor alkenylene chain and RcIt is as defined above for one or more
Aryl radical.The alkenylene moieties and aryl moiety of arylalkenyl independently can optionally be substituted selected from following group：
Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" aryloxy group " refers to-O-RcFree radical, wherein RcFor one or more aryl radicals as defined above, the virtue
Base section is optionally substituted selected from following group：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl,
Cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" cyclic hydrocarbon radical " refers to that the monocyclic or polycyclic hydrocarbon of the non-aromatic for the stabilization being only made of carbon and hydrogen atom is free
Base, it may include to condense or bridge loop system, have 3 to 15 carbon atoms (such as 3,4,5,6,7,8,9,10,11,12,13,
14 or 15 carbon atoms), preferably with 3 to 10 carbon atoms, and its be it is saturated or unsaturated and by singly-bound with
The remainder connection of molecule.Monocyclic free radical includes, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring
Octyl group.Polycyclic free radical includes, such as adamantyl, norborny, decahydro naphthyl etc..Cyclic hydrocarbon radical is optionally by selected from following
Group substitution：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" cycloalkylalkyl " refers to formula-RbRgFree radical, wherein RbFor alkylidene chain and RgFor cyclic hydrocarbon as defined above
Base, the alkylene moiety and cyclic hydrocarbon base section independently can optionally be substituted selected from following group：Alkyl, halogen, nitro,
Acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" heterocyclic radical " refers to 3 yuan to 18 yuan (such as 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 of stabilization
Or 18 yuan) non-aromatic ring free radical, it is by 2 to 12 carbon atoms (such as 2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms)
With 1 to 6 hetero atom (for example, 1,2,3,4,5,6 hetero atom) composition in nitrogen, oxygen and sulphur.Unless in the description
In addition illustrate, heterocyclic radical can be monocyclic, bicyclic, tricyclic or Fourth Ring loop system, it can include condensing or bridge joint ring system
System；And nitrogen, carbon or the sulphur atom in heterocyclic radical can be aoxidized optionally；Nitrogen-atoms is optionally quaternized；And heterocyclic radical can
With partially or completely saturation.The example of such heterocyclic radical includes but not limited to, dioxolanyl, bioxin base, thienyl [1,3]
Dithiane base, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidinyl, isothiazole alkyl, isoxazole alkyl, morpholinyl, octahydro indoles
Base, octahydro isoindolyl, 2- oxopiperazinyls, 2- oxo-piperidine bases, 2- oxo-pyrrolidines base, oxazole alkyl, piperidyl, piperazine
Base, 4- piperidone bases, piperazine cough up alkyl, pyrazolidinyl, quininuclidinyl, thiazolidinyl, 1, -5 (4H)-base of 2,4- Asia thiadiazoles, four
Hydrogen furyl, trioxa cyclohexyl, trithiane base, triazine alkyl, THP trtrahydropyranyl, thio-morpholinyl, thio-morpholinyl, 1- oxygen
Generation-thio-morpholinyl and 1,1- dioxo-thiomorpholinyl.Heterocyclic radical is optionally substituted selected from following group：Alkyl,
Halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" cycloheteroalkylalkyl " refers to formula-RbRhFree radical, wherein RbFor alkylidene chain and RhFor heterocycle as defined above
Base, and if heterocyclic radical is nitrogenous heterocyclic radical, heterocyclic radical can be connected at nitrogen-atoms with alkyl.The Asia of cycloheteroalkylalkyl
Alkyl chain part and heterocyclyl moieties are optionally substituted selected from following group：Alkyl, halogen, nitro, acyl group, acylamino-,
Epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" heteroaryl " refers to 5 yuan to 14 yuan (for example, 5,6,7,8,9,10,11,12,13 or 14 yuan) loop system free radicals,
It includes hydrogen atom, 1 to 13 carbon atom (for example, 1,2,3,4,5,6,7,8,9,10,11,12 or 13 carbon atom), 1 to 6
A (for example, 1,2,3,4,5,6 hetero atom) is selected from nitrogen, the hetero atom of oxygen and sulphur and at least one aromatic ring.For this
The purpose of invention, heteroaryl free radical can be monocyclic, two rings, tricyclic or Fourth Ring loop system, it can include fusion or bridge joint
Loop system；And nitrogen, carbon or the sulphur atom in heteroaryl can be aoxidized optionally；Nitrogen-atoms is optionally quaternized.Example
Including but not limited to, azepine cycloheptatriene base, acridinyl, benzimidazolyl, benzo [d] imidazole radicals, benzothiazolyl, benzo Yin
Diindyl base, benzodioxole base, benzofuranyl, benzoxazolyl, benzothiazolyl, benzo [d] isoxazolyls, benzo
Thiadiazolyl group, benzo [b] [Isosorbide-5-Nitrae] dioxepine base, Isosorbide-5-Nitrae-benzo dioxane base, benzo aphthofurans base,
Benzoxazolyl, benzodioxole group, benzene and bioxin base, benzopyranyl, chromene ketone group, benzofuran
Base, benzofuran ketone group, benzothienyl (benzothienyl), benzotriazole base, benzo [4,6] imidazo [1,2-a] pyridine
Base, benzoxazolinone base, benzimidazole sulfinyl, carbazyl, cinnoline base, dibenzofuran group, dibenzothiophene, furan
Mutter base, furanonyl, isothiazolyl, imidazo [1,2-a] pyridine radicals, imidazo [1,2-a] pyrimidine radicals, imidazo [1,2-a]
Pyrazinyl, imidazo [1,5-a] pyrazinyl, imidazole radicals, indyl, indazolyl, isoindolyl, indoline base, isoindoline base,
Isoquinolyl, indolizine base, isoxazolyls, naphthyridines Ji, oxadiazolyls, 2- oxo azatropylidene Ji, oxazolyls, Oxyranyle,
1- pyridine oxides base, 1- oxidation pyrimidine radicals, 1- oxidation pyrazinyl, 1- oxidation pyridazinyl, 1- phenyl -1H- pyrrole radicals, phenazinyl,
Phenothiazinyl, phenoxazine group, phthalazinyl, pteridyl, pteridine ketone group, purine radicals, pyrrole radicals, pyrazolyl, pyridine radicals, pyridone
Base, pyrazinyl, pyrimidine radicals, pyrimidine ketone group, pyridazinyl, pyrido [2,3-d] pyrimidine ketone group, pyrazolo [1,5-a] pyrimidine radicals, quinoline
Oxazoline base, quinazoline ketone group, quinoxalinyl, quinoxaline ketone group, quinolyl, isoquinolyl, tetrahydric quinoline group, thiazolyl, thiophene two
Oxazolyl, thieno [3,2-d] pyrimidin-4-one base, thieno [2,3-d] pyrimidin-4-one base, triazolyl, tetrazole radical, triazine radical with
And thienyl (i.e. thienyl).Heteroaryl is optionally substituted selected from following group：Alkyl, halogen, nitro, acyl group, acyl
Amino, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" heteroaryl alkyl " refers to formula-RbRiFree radical, wherein RbFor alkylidene chain and RiFor heteroaryl as defined above
Free radical.The alkylidene chain and heteroaryl moieties of heteroaryl alkyl independently can optionally be substituted selected from following group：Alkane
Base, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
" heteroarylalkenyl " refers to formula-RdRiFree radical, wherein RdFor alkenylene chain and RiFor heteroaryl as defined above
Base.The alkenylene chain part and heteroaryl moieties of heteroaryl alkyl independently can optionally be substituted selected from following group：Alkane
Base, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
Embodiment
This application involves the method for preparing the 3- indole ketone compounds represented by formula (I), it includes that aldehydes will be included
Compound, 2- aminobenzoic acid esters compounds or 2- aminophenyl acetic acids ester type compound, carboxylic acid compound and isocyanide class chemical combination
The mixture of thing adds solvent, and the mixture for adding solvent is heated；
Wherein, R1、R2、R3And R4It is each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, fragrant alkene
Base, aryloxy group, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl；
The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, arylalkenyl, aryloxy group, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical,
Cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl are optionally substituted selected from following group：Alkyl, halogen,
Nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl.
In presently filed embodiment, the described method includes：
Aldehyde compound, 2- aminobenzoic acid esters compounds or 2- aminophenyl acetic acids ester type compound, carboxylic acid will be included
The mixture of class compound and different cyanides adds the first solvent；
Optionally, stirred at normal temperatures to adding the mixture in the first solvent, by the first solvent concentration in mixture
Or remove, it will remove or the mixture of the first solvent of concentration added in the second solvent, and the mixture to adding the second solvent adds
Heat；
Wherein described first solvent and second solvent are identical or different.
In presently filed embodiment, the alkali for adding the second solvent is organic base or inorganic base, it may be selected from DBU (two
Azabicyclic), DIPA (diisopropanolamine (DIPA)), TEA (triethylamine), DIPEA (diisopropyl ethyl amine).
In presently filed embodiment, wherein by aldehyde compound, 2- aminobenzoic acid esters compounds or 2- amino
It is small that phenylacetic acid ester compound, carboxylic acid compound and different cyanides stir at least 0.5 in the first solvent at normal temperatures
When, for example, 0.5 to 12 it is small when, wherein mixing time can be 1 it is small when, 2 it is small when, 3 it is small when, 4 it is small when, 5 it is small when, 6 it is small when, 7 it is small when,
8 it is small when, 9 it is small when, 10 it is small when, 11 it is small when or 12 it is small when.
In presently filed embodiment, wherein residue is heated at least 5 minutes in the second solvent, such as 5-30 points
Clock, for example, heating 10,20 or 30 minutes, wherein the temperature heated be 100 DEG C to 200 DEG C, such as 110 DEG C, 120 DEG C, 130 DEG C,
140 DEG C, 150 DEG C, 160 DEG C, 170 DEG C, 180 DEG C, 190 DEG C or 200 DEG C.
In presently filed embodiment, the boiling point of first solvent is 20 to 200 DEG C.In presently filed embodiment
In, the boiling point of first solvent is 20 DEG C, 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C,
120 DEG C, 130 DEG C, 140 DEG C, 150 DEG C, 160 DEG C, 170 DEG C, 180 DEG C, 190 DEG C or 200 DEG C.
In presently filed embodiment, the boiling point of second solvent is higher or lower than the boiling point of the first solvent.At this
In the embodiment of application, the boiling point of second solvent is 20 to 200 DEG C.In presently filed embodiment, described second
The boiling point of solvent for 20 DEG C, 30 DEG C, 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C,
140 DEG C, 150 DEG C, 160 DEG C, 170 DEG C, 180 DEG C, 190 DEG C or 200 DEG C.
In presently filed embodiment, first solvent is selected from DMF, DMSO and alcohol, and the alcohol is selected from ethanol, isobutyl
Alcohol and trifluoroethanol.
In presently filed embodiment, second solvent is selected from DMF, DMSO, Isosorbide-5-Nitrae-dioxane and tetrahydrofuran.
In presently filed embodiment, before heating to the mixture, it is described add the first solvent mixture or
Alkali is added in the mixture for adding the second solvent.Wherein, the alkali can be organic base or inorganic base, for example, the alkali can
Selected from DBU, DIPA, TEA, DIPEA and NaHCO3。
In presently filed embodiment, wherein the aldehyde compound, 2- aminobenzoic acid esters compounds or 2- ammonia
The molar ratio of base phenylacetic acid ester compound, carboxylic acid compound and different cyanides is 0.9-1.1: 0.9-1.1: 0.9-
1.1: 0.9-1.1, for example, 1: 1: 1: 1.
In presently filed embodiment, the aldehyde compound, 2- aminobenzoic acid esters compounds or 2- aminobenzenes
Acetate compounds, carboxylic acid compound, the molar ratio of different cyanides and alkali are 0.9-1.1: 0.9-1.1: 0.9-1.1
: 0.9-1.1: 1.8-2.2, for example, 1: 1: 1: 1: 2.
In presently filed embodiment, the product obtained after heating is reacted is purified and/or dried.
In presently filed embodiment, the reaction solution obtained after heating is dissolved with ethyl acetate, is then eaten with saturation
Salt water washing, organic phase is dried with magnesium sulfate, is separated with silicagel column, obtains 3- indole ketone compounds.
In presently filed embodiment, the method undergoes following reaction process：
Wherein, R1、R2、R3And R4It is each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, fragrant alkene
Base, aryloxy group, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl；
The alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, arylalkenyl, aryloxy group, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical,
Cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl are optionally substituted selected from following group：Alkyl, halogen,
Nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical, heterocyclic radical and heteroaryl；R5For methyl or ethyl.
The application further relates to the 3- indole ketone compounds obtained by the present processes.
Present document relates to 3- indole ketone derivatives synthesis using multi-component reaction one kettle way, by reactant with certain
Ratio reaction, by shirtsleeve operation, a step purification after obtain target product.Method disclosed herein operation is more simple
Single, raw material is easy to get, and the compound of similar structures can be synthesized by the change of raw material mix.
In a detailed embodiment, preparation method described herein includes, in 10 milliliters of micro-wave oven reaction tube, first
2- Aminobenzoates or 2- aminophenyl acetic acids ester type compound (1.0 mMs) and aldehyde compound (1.0 mMs) is molten
Solution (solvent can also be DMF, DMSO, ethanol, isobutanol, trifluoroethanol) in 2.0 milliliters of methanol, then again by carboxylic acid
Class compound (1.0 mMs) and different cyanides (1.0 mMs) are sequentially added in the solution, and reaction solution stirs at normal temperatures
Mix overnight.Isocyanide compound is detected using thin-layer chromatography, when no remaining isocyanide raw material, reaction solution is blown using nitrogen
It is dry, then dissolved with 3.0 milliliters of dimethylformamide (DMF) (or DMSO, Isosorbide-5-Nitrae-dioxane or tetrahydrofuran make it is molten
Agent), add organic base or inorganic base (DBU, DIPA, TEA, DIPEA or NaHCO3Deng) (2.0 mMs), in micro-wave oven
Reacted 10 minutes at 150 DEG C.By obtained reaction solution using (50 milliliters) dissolvings of ethyl acetate, then washed with saturated common salt
Wash 3 times, every time 20 milliliters.After organic phase is dried using magnesium sulfate, separated using silicagel column, obtain 3- indole ketones and spread out
Biology.
Embodiment
The following example is provided for the nonrestrictive purpose illustrated.The following example discloses generation of the invention
The determination data of the compounds process for production thereof of table and obtained compound.
The preparation of embodiment 1 --- compound 1
1- benzoyl-N- benzyls -3- oxos -2-phenylindone quinoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and benzene first
Aldehyde (105 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of methanol, then again by benzoic acid (122 milligrams, 1.0 mMs)
Sequentially add in the solution, be stirred overnight under reaction solution room temperature, then using thin layer with benzyl isocyanide (122 microlitres, 1.0 mMs)
Chromatography detects, and when no remaining isocyanide raw material, reaction solution is dried up using nitrogen, is then dissolved again with 3.0 milliliters of DMF,
DBU (298 microlitres, 2.0 mMs) is added, is reacted 10 minutes at 150 DEG C in micro-wave oven.The reaction solution uses ethyl acetate
(50 milliliters) dissolvings, then with saturated common salt water washing 3 times, every time 20 milliliters.After organic phase is dried using magnesium sulfate, use
Silicagel column is separated, and obtains compound 1.
1H NMR (400MHz, DMSO) δ 9.93 (s, 1H), 8.06-7.97 (m, 2H), 7.90 (dd, J=7.7,1.6Hz,
1H), 7.58 (tdd, J=3.9,2.7,1.5Hz, 2H), 7.50 (d, J=7.8Hz, 2H), 7.48-7.39 (m, 6H), 7.30 (d,
J=6.7Hz, 3H), 7.26-7.22 (m, 2H), 7.16 (t, J=7.4Hz, 1H), 5.64 (d, J=16.6Hz, 1H), 5.26 (d,
J=16.7Hz, 1H).
13C NMR (100MHz, DMSO) δ 190.6,170.4,167.8,141.5,136.7,136.6,133.1,132.9,
132.4,130.1,129.9,129.4,129.0,128.7,128.6,128.5,127.6,127.1,123.7,121.1,
116.9,79.6,72.6,45.9.
The preparation of embodiment 2 --- compound 2
1- benzoyl-N- benzyls -2- (4- methoxyphenyls) -3--oxindole quinoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and to first
Epoxide benzaldehyde (121 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of trifluoroethanol, then again by benzoic acid (122 millis
Gram, 1.0 mMs) and benzyl isocyanide (122 microlitres, 1.0 mMs) sequentially add in the solution, it is stirred under reaction solution room temperature
At night, then detect isocyanide compound using thin-layer chromatography, when no remaining isocyanide raw material, reaction solution be concentrated under reduced pressure, so
Dissolved again with 3.0 milliliters of DMSO afterwards, add DIPA (2.0 mMs), reacted 15 minutes at 180 DEG C in micro-wave oven.This is anti-
Liquid is answered using the dissolving of (50 milliliters) of ethyl acetate, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase is used
After magnesium sulfate drying, separated using silicagel column, obtain compound 2.
1H NMR (400MHz, DMSO) δ 9.82 (s, 1H), 8.04-7.97 (m, 2H), 7.90 (dd, J=7.7,1.5Hz,
1H), 7.60-7.53 (m, 2H), 7.49 (t, J=7.6Hz, 2H), 7.33 (dd, J=16.6,8.0Hz, 6H), 7.22 (dd, J=
11.1,5.3Hz, 2H), 7.15 (t, J=7.5Hz, 1H), 6.97 (d, J=9.0Hz, 2H), 5.62 (d, J=16.6Hz, 1H),
5.25 (d, J=16.6Hz, 1H), 3.74 (s, 3H).
13C NMR (100MHz, DMSO) δ 190.7,170.4,167.7,160.5,141.4,136.6,136.5,133.0,
132.4,130.0,129.0,128.7,128.6,128.5,127.6,127.1,124.4,123.6,121.2,116.9,
114.9,72.2,55.8,45.9.
The preparation of embodiment 3 --- compound 3
N- benzyls -1- (4- chlorobenzoyls) -3- oxos -2-phenylindone quinoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and benzene first
Aldehyde (105 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of ethanol, then again by parachlorobenzoic-acid (157 milligrams, 1.0 mmoles
You) and benzyl isocyanide (122 microlitres, 1.0 mMs) sequentially add in the solution, be stirred overnight under reaction solution room temperature, then use
Thin-layer chromatography detects isocyanide compound, when no remaining isocyanide raw material, reaction solution is dried up using nitrogen, is then used again
3.0 milliliters of DMF dissolvings, add TEA (2.0 mMs), are reacted 10 minutes at 150 DEG C in micro-wave oven.The reaction solution uses
(50 milliliters) of ethyl acetate dissolving, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase is done using magnesium sulfate
After dry, separated using silicagel column, obtain compound 3.
1H NMR (400MHz, DMSO) δ 10.01 (s, 1H), 8.31 (s, 1H), 8.03 (d, J=8.6Hz, 2H), 7.94-
7.85 (m, 1H), 7.63-7.53 (m, 3H), 7.47-7.40 (m, 5H), 7.30 (d, J=6.4Hz, 3H), 7.26-7.20 (m,
2H), 7.16 (t, J=7.5Hz, 1H), 5.64 (d, J=16.7Hz, 1H), 5.26 (d, J=16.7Hz, 1H).
13C NMR (100MHz, DMSO) δ 190.5,170.2,166.8,141.5,137.3,136.7,136.5,132.9,
131.7,130.6,130.0,129.5,129.0,128.8,128.5,127.6,127.1,123.7,121.1,117.0,79.7,
72.7 46.0.
The preparation of embodiment 4 --- compound 4
1- benzoyls-N- benzyl -3- oxos -2- (p-methylphenyl) indoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and to first
Benzaldehyde (118 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of isobutanol, then again by benzoic acid (122 milligrams, 1.0
MM) and benzyl isocyanide (122 microlitres, 1.0 mMs) sequentially add in the solution, be stirred overnight under reaction solution room temperature, then
Isocyanide compound is detected using thin-layer chromatography, when no remaining isocyanide raw material, reaction solution is dried up using nitrogen, Ran Houzai
Dissolved with 3.0 milliliters of DMF, add DIPEA (2.0 mMs), reacted 10 minutes at 150 DEG C in micro-wave oven.The reaction solution
Using the dissolving of (50 milliliters) of ethyl acetate, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase is used into sulfuric acid
After magnesium drying, separated using silicagel column, obtain compound 4.
1H NMR (400MHz, CDCl3) δ 8.07 (dd, J=7.8,1.6Hz, 1H), 7.90-7.84 (m, 2H), 7.51 (t, J
=7.4Hz, 1H), 7.47-7.38 (m, 5H), 7.33-7.22 (m, 6H), 7.16 (d, J=8.2Hz, 2H), 7.09 (dd, J=
13.2,5.4Hz, 2H), 7.01 (d, J=8.4Hz, 1H), 5.43 (s, 2H), 2.32 (s, 3H).
13C NMR (100MHz, CDCl3) δ 190.2,169.8,167.5,141.8,140.0,135.9,135.8,132.6,
132.1,130.2,129.0,128.9,128.5,127.6,127.3,126.5,123.2,121.3,116.0,72.0,46.9,
21.1。
The preparation of embodiment 5 --- compound 5
1- benzoyls -2- (4- methoxyphenyls) -3- oxo-N- phenethyl indoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and to first
Epoxide benzaldehyde (121 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of trifluoroethanol, then again by benzoic acid (122 millis
Gram, 1.0 mMs) and phenethyl isocyanide (110 microlitres, 1.0 mMs) sequentially add in the solution, stirred under reaction solution room temperature
Overnight, isocyanide compound then is detected using thin-layer chromatography, when no remaining isocyanide raw material, reaction solution is blown using nitrogen
It is dry, then dissolved again with 3.0 milliliters of DMF, add NaHCO3(2.0 mMs), react 10 points in micro-wave oven at 150 DEG C
Clock.The reaction solution is using the dissolving of (50 milliliters) of ethyl acetate, then with saturated common salt water washing 3 times, every time 20 milliliters.Will be organic
After mutually being dried using magnesium sulfate, separated using silicagel column, obtain compound 5.
1H NMR (400MHz, CDCl3) δ 8.13-8.05 (m, 1H), 7.86 (d, J=7.4Hz, 2H), 7.63-7.49 (m,
2H), 7.42 (dd, J=12.2,8.4Hz, 4H), 7.31 (d, J=4.3Hz, 4H), 7.27-7.22 (m, 2H), 7.13 (t, J=
7.6Hz, 2H), 7.01 (s, 1H), 6.86 (d, J=8.9Hz, 2H), 4.56-4.17 (m, 2H), 3.77 (s, 3H), 3.06 (td, J
=9.7,6.1Hz, 2H).
13C NMR (100MHz, CDCl3) δ 190.1,169.2,167.4,160.6,141.7,138.2,135.9,132.6,
132.1,129.3,129.0,128.9,128.7,128.5,127.6,126.7,124.8,123.1,121.3,114.9,
114.8,71.6,55.4,45.0,33.5.
The preparation of embodiment 6 --- compound 6
1- (4- chlorobenzoyls) -3- oxos-N- phenethyls -2-phenylindone quinoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and benzene first
Aldehyde (105 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of ethanol, then again by parachlorobenzoic-acid (157 milligrams, 1.0 mmoles
You) and phenethyl isocyanide (110 microlitres, 1.0 mMs) sequentially add in the solution, be stirred overnight under reaction solution room temperature, then
Isocyanide compound is detected using thin-layer chromatography, when no remaining isocyanide raw material, reaction solution is dried up using nitrogen, Ran Houzai
Dissolved with 3.0 milliliters of DMF, add DBU (298 microlitres, 2.0 mMs), reacted 10 minutes at 150 DEG C in micro-wave oven.Should
Reaction solution is using the dissolving of (50 milliliters) of ethyl acetate, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase is made
After being dried with magnesium sulfate, separated using silicagel column, obtain compound 6.
1H NMR (400MHz, CDCl3) δ 8.06 (dd, J=8.0,1.5Hz, 1H), 7.80 (d, J=8.5Hz, 2H),
7.61-7.44 (m, 4H), 7.41 (d, J=8.5Hz, 2H), 7.38-7.34 (m, 3H), 7.31 (d, J=4.3Hz, 4H), 7.27-
7.21 (m, 3H), 7.18-7.10 (m, 2H), 7.03 (s, 1H), 4.57-4.17 (m, 2H), 3.06 (tt, J=13.5,6.9Hz,
2H)。
13C NMR (100MHz, CDCl3) δ 190.0,169.0,166.5,141.8,138.5,138.1,136.1,133.3,
129.9,129.6,129.4,129.0,128.9,128.7,127.5,126.8,123.3,121.2,114.9,72.1,45.1,
33.5。
The preparation of embodiment 7 --- compound 7
1- formoxyl -3- oxos-N- phenethyls -2-phenylindone quinoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and benzene first
Aldehyde (105 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of trifluoroethanol, then again by formic acid (38 microlitres, 1.0 mMs)
Sequentially added with phenethyl isocyanide (110 microlitres, 1.0 mMs) in the solution, be stirred overnight under reaction solution room temperature, then use
Thin-layer chromatography detects isocyanide compound, when no remaining isocyanide raw material, reaction solution is dried up using nitrogen, is then used again
3.0 milliliters of DMF dissolvings, add DBU (298 microlitres, 2.0 mMs), are reacted 10 minutes at 150 DEG C in micro-wave oven.This is anti-
Liquid is answered using the dissolving of (50 milliliters) of ethyl acetate, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase is used
After magnesium sulfate drying, separated using silicagel column, obtain compound 7.
1H NMR (400MHz, CDCl3) δ 8.63-8.49 (m, 2H), 7.86-7.71 (m, 2H), 7.37-7.32 (m, 1H),
7.31 (s, 1H), 7.30-7.26 (m, 3H), 7.25 (d, J=3.7Hz, 1H), 7.24-7.21 (m, 1H), 7.21-7.12 (m,
3H), 7.11-6.99 (m, 2H), 3.81-3.68 (m, 1H), 3.67-3.54 (m, 1H), 2.89 (td, J=7.0,4.2Hz, 2H).
13C NMR (101MHz, CDCl3) δ 196.38,163.49,162.10,153.03,138.99,138.12,
136.03,129.55,128.74,128.70,126.92,126.73,125.07,124.78,121.24,118.18,41.62,
35.32。
The preparation of embodiment 8 --- compound 8
N- benzyl -1- formoxyls -3- oxos -2-phenylindone quinoline -2- formamides
In 10 milliliters of micro-wave oven reaction tube, first by 2- Aminobenzoates (129 microlitres, 1.0 mMs) and benzene first
Aldehyde (105 microlitres, 1.0 mMs) is dissolved in 2.0 milliliters of trifluoroethanol, then again by formic acid (38 microlitres, 1.0 mMs)
Sequentially add in the solution, be stirred overnight under reaction solution room temperature, then using thin layer with benzyl isocyanide (122 microlitres, 1.0 mMs)
Chromatography detects isocyanide compound, and when no remaining isocyanide raw material, reaction solution is dried up using nitrogen, then again with 3.0 millis
DMF dissolvings are risen, DBU (298 microlitres, 2.0 mMs) is added, is reacted 10 minutes at 150 DEG C in micro-wave oven.The reaction solution makes
With the dissolving of (50 milliliters) of ethyl acetate, then with saturated common salt water washing 3 times, every time 20 milliliters.Organic phase is used into magnesium sulfate
After drying, separated using silicagel column, obtain compound 8.
1H NMR (400MHz, CDCl3) δ 8.68-8.52 (m, 2H), 7.84-7.74 (m, 2H), 7.48 (d, J=5.4Hz,
1H), 7.35 (dd, J=6.9,2.5Hz, 3H), 7.32 (s, 2H), 7.29 (dd, J=14.2,6.8Hz, 4H), 7.19-7.13
(m, 2H), 4.65 (dd, J=14.7,5.9Hz, 1H), 4.49 (dd, J=14.7,5.6Hz, 1H).
13C NMR (101MHz, CDCl3) δ 196.45,163.58,162.05,153.11,139.07,136.95,
136.32,129.68,129.59,128.87,127.97,127.89,127.03,125.10,124.85,121.28,118.22,
44.52。
Claims (11)
1. preparing the method for the 3- indole ketone compounds represented by formula (I), it includes：
Aldehyde compound, 2- aminobenzoic acid esters compounds or 2- aminophenyl acetic acids ester type compound, carboxylic acids will be included
The mixture of compound and different cyanides adds solvent, and the mixture for adding the solvent is heated；
Wherein, R1、R2、R3And R4It is each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, arylalkenyl, virtue
Epoxide, cyclic hydrocarbon radical, cycloalkylalkyl, heterocyclic radical, cycloheteroalkylalkyl, heteroaryl, heteroaryl alkyl or heteroarylalkenyl；Above base
Group is optionally substituted selected from following group：Alkyl, halogen, nitro, acyl group, acylamino-, epoxide, sulfenyl, aryl, cyclic hydrocarbon radical,
Heterocyclic radical and heteroaryl.
2. the method as described in claim 1, wherein the mixture is added the first solvent, optionally to adding the first solvent
Mixture stir at normal temperatures, first solvent concentration in the mixture or removal will remove or concentration first
The mixture of solvent adds the second solvent and simultaneously the mixture for adding the second solvent is heated, first solvent and described second molten
Agent is identical or different.
3. method as claimed in claim 2, wherein when the stirring progress 0.5 to 12 is small, the heating carries out 5-30 minutes,
Preferably heat 10 minutes.
4. method as claimed in claim 2, wherein being heated at a temperature of 100 DEG C to 200 DEG C, adds preferably at 150 DEG C
Heat.
5. method as claimed in claim 2, wherein first solvent is selected from DMF, DMSO and alcohol, preferably described alcohol is selected from
Methanol, ethanol, isobutanol and trifluoroethanol.
6. method as claimed in claim 2, wherein second solvent is selected from DMF, DMSO, Isosorbide-5-Nitrae-dioxane and tetrahydrochysene furan
Mutter.
7. the method as described in any one of claim 1-6, wherein to the mixture, the addition before the heating
Alkali is added in the mixture of first solvent or the mixture for adding the second solvent, preferably described alkali is organic base or inorganic
Alkali, more preferably described alkali are selected from DBU, DIPA, TEA, DIPEA and NaHCO3。
8. the method as described in any one of claim 1-7, wherein the aldehyde compound, 2- aminobenzoic acid esters
Compound or 2- aminophenyl acetic acids ester type compound, the molar ratio of carboxylic acid compound and different cyanides are 0.9-1.1: 0.9-
1.1: 0.9-1.1: 0.9-1.1, it is therefore preferable to 1: 1: 1: 1.
9. method as claimed in claim 7 or 8, wherein the aldehyde compound, 2- aminobenzoic acid esters compounds or 2-
Aminophenyl acetic acid ester type compound, carboxylic acid compound, the molar ratio of different cyanides and alkali are 0.9-1.1: 0.9-1.1:
0.9-1.1: 0.9-1.1: 1.8-2.2, it is therefore preferable to 1: 1: 1: 1: 2.
10. method as claimed in any one of claims 1-9 wherein, wherein the method undergo following reaction process：
Wherein, R5For methyl or ethyl.
11. the 3- indole ketone compounds obtained as the method any one of claim 1-10.
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