CN109422699A - A kind of synthetic method of alpha-keto amide class compound - Google Patents
A kind of synthetic method of alpha-keto amide class compound Download PDFInfo
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Abstract
The invention discloses a kind of synthetic methods of alpha-keto amide class compound: isonitrile shown in quinoxaline -2- formaldehyde, formula II shown in formula I is dissolved in organic solvent, under the action of copper catalyst and oxidant, it is reacted 12~30 hours in 50~90 DEG C, gained reaction solution is post-treated to obtain alpha-keto amide class compound shown in formula III；The copper catalyst is copper trifluoromethanesulfcomposite or copper tetrafluoroborate, and the copper tetrafluoroborate is added in form of an aqueous solutions；The oxidant is one of selenium dioxide, the chloro- 5,6- dicyano -1,4- benzoquinones of 2,3- bis- or iodic anhydride or more than one mixture.Raw material of the present invention is simple and easy to get；Catalyst is cheap and easy to get, and low toxicity efficiently, and is assisted without extra ligand；Reaction condition is milder, saves energy consumption；The features such as in addition, also having yield high, substrate universality is strong, easy to operate.
Description
(1) technical field
The present invention relates to a kind of synthetic method of organic compound, a kind of alpha-keto amide class compound is related in particular to
Synthetic method.
(2) background technique
Alpha-keto amide is the core skeleton structure of bioactive substance, synthetic drug and natural drug, while being also synthesis
The key intermediate of some important compounds.(referring to Chem.Rev., 1997,97,2243；Eur. J.Med.Chem.,
2000,35,887.)。
Currently, the method for traditional synthesis alpha-keto amide is the aminolysis using 2-ketoacid.This kind of reaction needs a large amount of de-
Aqua and reaction condition is more harsh, efficiency is lower, and the Atom economy reacted is not high, and simultaneous reactions substrate has biggish
Limitation (referring to J.Org.Chem., 2003,68,6063).Therefore, using raw material cheap and easy to get, develop the synthesis of green high-efficient
Route has great importance.In recent years, realize that alpha-keto amide synthesizes to have obtained extensive development using catalytic condition.Such as
Halogenated aryl hydrocarbon realized by transition metal-catalyzed carbonylation aminating reaction this kind of amide synthesis (referring to Org.Lett.,
2009,11,1321).Then, aryl acetylene compound under oxidative conditions also realize alpha-keto amide synthesis (referring to
J.Am.Chem.Soc.,20 10,132,28).With going deep into for research, 2-ketoacid realizes α-by the oxidative condensation being catalyzed
The synthesis of keto-aldehyde, in these reactions, tertiary amine or amide such as DMF etc. provide amine source by the activation of c h bond for reaction
(referring to Org.Biomol.Chem., 2013,11,3649.).α -one aldehyde is real by oxidative dehydrogenation coupling reaction and aminated compounds
Existing this kind of amide efficiently synthesizes (Org.Lett., 2012,14,3280).It is water, the original of reaction that this kind of reaction, which has by-product,
The features such as subeconomy is high, and by-product cleans.In addition, the direct oxidation by amide can also obtain this kind of alpha-keto amide chemical combination
(Tetrahedron Lett., 2007,48,8 982) for object.
Although the method for having developed a variety of synthesis alpha-keto amide class compounds, there are still some for these synthetic methods
Deficiency, for example, the use of heavy metal catalyst, reaction raw materials be not easy to obtain and reaction condition it is relatively harsh etc..Therefore, send out
Open up that a kind of raw material is easy to get, reaction condition is mild and the method for environmental-friendly synthesis alpha-keto amide still has certain challenge.
(3) summary of the invention
For the deficiencies in the prior art, the present invention is intended to provide a kind of method of alpha-keto amide class compound, gram
The shortcomings that taking the prior art, using the expensive noble metal of base metal substitution, using aldehydes simple and easy to get as raw material, using isonitrile as amine
Source, water are oxygen source, and realize and reacted under the conditions of relatively mild.
A kind of synthetic method of alpha-keto amide class compound, the method specifically carry out as follows:
Isonitrile shown in quinoxaline -2- formaldehyde, formula II shown in formula I is dissolved in organic solvent, in copper catalyst and oxygen
Under the action of agent, reacted 12~30 hours in 50~90 DEG C, gained reaction solution is post-treated to obtain α -one acyl shown in formula III
Aminated compounds；The substance of isonitrile, copper catalyst and oxidant shown in quinoxaline -2- formaldehyde, formula II shown in the formula I
The ratio between amount be 1:1~2:0.05~0.2:1；The copper catalyst be copper trifluoromethanesulfcomposite or copper tetrafluoroborate, it is described
Copper tetrafluoroborate is added in form of an aqueous solutions；The oxidant is selenium dioxide, the chloro- 5,6- dicyan of 2,3- bis-
One of base -1,4- benzoquinones or iodic anhydride or more than one mixture；
In formula I or formula III,
R1For CH3, Cl or Br；R2For H, CH3、OCH3, F, Cl, Br or CF3；
n1~n2For the number of substituent group, n1For 1~4, n2It is 1~5；
In formula II,
Further, the organic solvent be one of toluene, 1,2- dichloroethanes, nitromethane or more than one
Mixed solvent, preferably 1,2- dichloroethanes.
Further, the additional amount of the organic solvent is with the amount of the substance of quinoxaline -2- formaldehyde shown in the formula I
It is calculated as 10ml/mmol.
Further, the preferably described oxidant is selenium dioxide.
Further, the preferably described catalyst is copper tetrafluoroborate, and the copper tetrafluoroborate is generally the four of 45%wt
Cupric fluoborate aqueous solution form is added.
Further, preferably, the reaction temperature is 80 DEG C, the reaction time is 18 hours.
Further, quinoxaline -2- formaldehyde and the ratio between the amount of substance of copper catalyst shown in the preferably described formula I
For 1:0.1.
Further, the R3ForWhen, the object of isonitrile shown in quinoxaline -2- formaldehyde and formula II shown in formula I
The ratio between amount of matter is 1:2.
Further, recommend the post-processing approach of the reaction solution are as follows: after reaction, be added into gained reaction solution
The column chromatography silica gel of 100-200 mesh is simultaneously evaporated under reduced pressure removing solvent, gained crude product is carried out silica gel column chromatography separation, and with body
Product is than being that the petroleum ether of 30:1 and the mixture of ethyl acetate are eluted as eluant, eluent, and TLC tracks elution process, and collection contains
There is the eluent of target product, merges the eluent solvent is evaporated off and obtain alpha-keto amide class compound shown in formula III.
Further, method of the present invention is recommended specifically to carry out as follows:
Using isonitrile shown in quinoxaline -2- formaldehyde, formula II shown in formula I as starting material, it is dissolved in organic solvent, is urged in copper
Under the action of agent and oxidant, is reacted in 80 DEG C 18 hours, after reaction, 100-200 mesh is added into gained reaction solution
Column chromatography silica gel and be evaporated under reduced pressure removing solvent, by gained crude product carry out silica gel column chromatography separation, and with volume ratio be 30:
1 petroleum ether and the mixture of ethyl acetate are eluted as eluant, eluent, and TLC tracks elution process, are collected and are produced containing target
The eluent of object, merges the eluent solvent is evaporated off and obtain alpha-keto amide class compound shown in formula III；I institute of formula
The ratio between amount of substance of isonitrile shown in the quinoxaline -2- formaldehyde that shows, formula II, copper catalyst and oxidant is 1:1~2:0.1:
1；The copper catalyst is the aqueous solution of the copper tetrafluoroborate of 45%wt；The oxidant is selenium dioxide；Described has
Solvent is 1,2- dichloroethanes；The additional amount of the organic solvent is with the object of quinoxaline -2- formaldehyde shown in the formula I
The amount of matter is calculated as 10ml/mmol.
The raw material 3- phenyl-quinoxaline -2- formaldehyde that the present invention uses, those skilled in the art can be according to existing literature public affairs
The method opened voluntarily is prepared, such as document [Jarikote, Dilip V.et al, Bioorganic &Medicinal
Chemistry, 2011,19,826-835] etc..
Compared with prior art, the beneficial effects of the present invention are:
Raw material of the present invention is simple and easy to get；Catalyst is cheap and easy to get, and low toxicity efficiently, and is assisted without extra ligand；React item
Part is milder, saves energy consumption；The features such as in addition, also having yield high, substrate universality is strong, easy to operate.
(4) specific implementation method
Invention is further described in detail combined with specific embodiments below, but protection scope of the present invention is not limited to
This:
The synthetic method for the raw material quinoxaline -2- formaldehyde that the present invention uses:
(1) acetophenone compounds (20mmol) and 100mL ether are added in the round-bottomed flask of 250mL, are dripped under ice bath
Liquid feeding bromine (22mmol, 1.07mL) is added dropwise rear solution and rufous is presented, remove ice bath, stirs 1 hour at room temperature, reddish brown
Color gradually takes off, and uses NaS after reaction2O3Solution washes away extra bromine, is extracted with ether, anhydrous Na2SO4It is dry, mistake
Filter, vacuum distillation remove solvent, and the alpha-brominated phenylpropyl alcohol ketone class compound of gained crude product is not required to be further purified, can be directly used for down
One step.
(2) by alpha-brominated propiophenone (20mmol), HClO obtained by step (1)4-SiO4(2.6g) and 100mL acetonitrile are added
In the round-bottomed flask of 250mL, under magnetic stirring, corresponding o-phenylenediamine is dissolved in 20mL acetonitrile, is added drop-wise to round bottom burning
In bottle, stirs, detected with TLC at room temperature, until fully reacting (it is generally necessary to 2-3 days), filtering, wash filter residue with methylene chloride,
The column chromatography silica gel of 100-200 mesh is added into filtrate and is evaporated under reduced pressure removing solvent, gained crude product is subjected to silica gel column layer
Analysis separation, and eluted using volume ratio for the petroleum ether of 20:1 and the mixture of ethyl acetate as eluant, eluent, collect elution
TLC tracks elution process to liquid simultaneously, and solvent is evaporated off in the obtained eluent containing target product and obtains product 2- methyl quinoline
Quinoline sterling.
(3) selenium dioxide (18mmol, 2g), Isosorbide-5-Nitrae-dioxane of 80mL and 5mL water are added in round-bottomed flask, heating
Selenium dioxide is dissolved, 2- methyl-quinoxaline obtained by step (2) is then added, is heated to 105 DEG C, is flowed back 5 hours.TLC detection
Reaction uses diatomite drainage after reaction, washs filter residue with methylene chloride, merging filtrate is added a large amount of water, uses methylene chloride
Extraction, merge organic layer simultaneously the column chromatography silica gel of 100-200 mesh is added and is evaporated under reduced pressure removing solvent, by gained crude product into
The separation of row silica gel column chromatography, and washed using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent
De-, collecting eluent, TLC tracks elution process simultaneously, and solvent is evaporated off in the obtained eluent containing target product and obtains product
Quinoxaline -2- formaldehyde sterling.
The raw material isonitrile that the present invention uses is prepared in accordance with the following steps:
Bromophenyl aminated compounds (8mmol): will be placed in round-bottomed flask by step I, and first is added as solvent in tetrahydrofuran
Acetic anhydride (1.5mL), 0 DEG C of reaction 2h.Saturated solution of sodium bicarbonate is quenched, and ethyl acetate extraction, anhydrous magnesium sulfate is dry, rotation
It is dry, it obtains N- phenyl formamide class compound and is directly used in next step without further purification.
Step II: being added tetrahydrofuran (13 mL) in the product N- phenyl formamide class compound that step I is obtained, and three
Ethamine (6.9mL), phosphorus oxychloride (1.2mL) is added dropwise in the mixed liquor of front under ice bath, 0 DEG C of reaction 2h.Sodium bicarbonate is full
It is quenched with solution, methylene chloride extraction, anhydrous magnesium sulfate is dry, is spin-dried for, and crossing column can be obtained product isonitrile.
Embodiment 1
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), the iodo- 4- isonitrile base benzene of 0.3mmol 1-
The tetrafluoro boric acid copper liquor (22.8mg) of (68.7mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45%wt add
Enter into 15mL heavy wall pressure resistance reaction tube, adds 3mL 1,2- methylene chloride as solvent.Then, the magnetic agitation 18 at 80 DEG C
Hour, two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, gained crude product is subjected to silica gel column chromatography
Separation, and eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracking is washed
De- process collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is
Yellow solid, yield 65%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.74(s,1H),8.25(dd,J1=8.5Hz, J2=
1.0Hz,1H),8.23(dd,J1=8.5Hz, J2=1.0Hz, 1H), 7.94-7.91 (m, 1H), 7.88-7.84 (m, 1H),
7.74–7.72(m,2H),7.67–7.64(m,2H), 7.52–7.47(m,3H),7.33–7.31(m,2H)；13C NMR
(125MHz,CDCl3):δ 189.8,157.6,152.6,148.4,142.4,140.0,138.2,137.2,135.8,132.3,
130.8,130.1,129.7,129.5,129.12,129.10,121.7,89.3；
Embodiment 2
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), the iodo- 4- isonitrile base benzene of 0.3mmol 1-
(68.7mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol copper trifluoromethanesulfcomposite (10. 9mg) are added to 15mL heavy wall
In pressure-resistant reaction tube, 3mL 1,2- methylene chloride as solvent are added.Then, magnetic agitation 18 hours at 80 DEG C.To gained
Two spoon column chromatography silica gels (100-200 mesh) is added in reaction solution, by the progress silica gel column chromatography separation of gained crude product, and with
Volume ratio is that the petroleum ether of 30:1 and the mixture of ethyl acetate are eluted as eluant, eluent, and TLC tracks elution process, collects
Eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is yellow solid, is produced
Rate 35%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.74(s,1H),8.25(dd,J1=8.5Hz, J2=
1.0Hz,1H),8.23(dd,J1=8.5Hz, J2=1.0Hz, 1H), 7.94-7.91 (m, 1H), 7.88-7.84 (m, 1H),
7.74–7.72(m,2H),7.67–7.64(m,2H), 7.52–7.47(m,3H),7.33–7.31(m,2H)；13C NMR
(125MHz,CDCl3):δ189.8,157.6,152.6,148.4,142.4,140.0,138.2,137.2,135.8,132.3,
130.8,130.1,129.7,129.5,129.12,129.10,121.7,89.3；
Embodiment 3
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), the iodo- 4- isonitrile base benzene of 0.3mmol 1-
The tetrafluoro boric acid copper liquor (11.4mg) of (68.7mg), 0.3mmol selenium dioxide (33.3mg) and 0.015mmol 45%wt
It is added in 15mL heavy wall pressure resistance reaction tube, adds 3mL 1,2- methylene chloride as solvent.Two are added into gained reaction solution
Gained crude product is carried out silica gel column chromatography separation, and is the stone of 30:1 with volume ratio by spoon column chromatography silica gel (100-200 mesh)
The mixture of oily ether and ethyl acetate is eluted as eluant, eluent, and TLC tracks elution process, collects washing containing target product
De- liquid, merges the eluent solvent is evaporated off and obtain target product.The substance is yellow solid, yield 43%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.74(s,1H),8.25(dd,J1=8.5Hz, J2=
1.0Hz,1H),8.23(dd,J1=8.5Hz, J2=1.0Hz, 1H), 7.94-7.91 (m, 1H), 7.88-7.84 (m, 1H),
7.74–7.72(m,2H),7.67–7.64(m,2H), 7.52–7.47(m,3H),7.33–7.31(m,2H)；13C NMR
(125MHz,CDCl3):δ 189.8,157.6,152.6,148.4,142.4,140.0,138.2,137.2,135.8,132.3,
130.8,130.1,129.7,129.5,129.12,129.10,121.7,89.3；
Embodiment 4
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), the iodo- 4- isonitrile base benzene of 0.3mmol 1-
The tetrafluoro boric acid copper liquor (45.6mg) of (68.7mg), 0.3mmol selenium dioxide (33.3mg) and 0.06mmol 45%wt add
Enter into 15mL heavy wall pressure resistance reaction tube, adds 3mL 1,2- methylene chloride as solvent.Then, the magnetic agitation 18 at 80 DEG C
Hour.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, gained crude product is subjected to silica gel column chromatography
Separation, and eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracking is washed
De- process collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is
Yellow solid, yield 56%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.74(s,1H),8.25(dd,J1=8.5Hz, J2=
1.0Hz,1H),8.23(dd,J1=8.5Hz, J2=1.0Hz, 1H), 7.94-7.91 (m, 1H), 7.88-7.84 (m, 1H),
7.74–7.72(m,2H),7.67–7.64(m,2H), 7.52–7.47(m,3H),7.33–7.31(m,2H)；13C NMR
(125MHz,CDCl3):δ 189.8,157.6,152.6,148.4,142.4,140.0,138.2,137.2,135.8,132.3,
130.8,130.1,129.7,129.5,129.12,129.10,121.7,89.3；
Embodiment 5
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), 0.3mmol 1- ethyl -3- isonitrile base benzene
The tetrafluoro boron of (39.3mg), 0.3mmol 2,3- bis- chloro- 5,6- dicyano -1,4- benzoquinones (68.1mg) and 0.03 mmol 45%
Sour copper liquor (22.8mg) is added in 15mL heavy wall pressure resistance reaction tube, adds 3mL 1,2- methylene chloride as solvent.It connects
, magnetic agitation 18 hours at 80 DEG C.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, by institute
Crude product carry out silica gel column chromatography separation, and using volume ratio for 30:1 petroleum ether and ethyl acetate mixture as elute
Agent is eluted, and TLC tracks elution process, collects the eluent containing target product, merges the eluent and solvent is evaporated off
Obtain target product.The substance is yellow solid, yield 52%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.73(s,1H),8.27–8.24(m,2H), 7.94–7.91
(m,1H),7.88–7.85(m,1H),7.77–7.76(m,3H),7.55 –7.50(m,3H),7.25–7.15(m,3H),2.65
(q, J=7.5Hz, 2H), 1.28 (t, J=7.5Hz, 3H)；13C NMR(125MHz,CDCl3):δ190.8,157.6,152.7,
148.9, 142.6,140.2,137.6,134.9,133.4,132.1,130.7,130.0,129.8,129.6, 129.2
(2C),128.9,126.9,126.3,122.4,24.3,14.0；
Embodiment 6
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), 0.3mmol 1- ethyl -3- isonitrile base benzene
The tetrafluoro boric acid copper liquor (22.8mg) of (39.3mg), 0.3mmol iodic anhydride (100.1mg) and 0.03mmol 45%
It is added in 15mL heavy wall pressure resistance reaction tube, adds 3mL 1,2- methylene chloride as solvent.Then, the magnetic agitation at 80 DEG C
18 hours.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, gained crude product is subjected to silica gel column layer
Analysis separation, and eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracking
Elution process collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance
For yellow solid, yield 54%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.73(s,1H),8.27–8.24(m,2H), 7.94–7.91
(m,1H),7.88–7.85(m,1H),7.77–7.76(m,3H),7.55 –7.50(m,3H),7.25–7.15(m,3H),2.65
(q, J=7.5Hz, 2H), 1.28 (t, J=7.5Hz, 3H)；13C NMR(125MHz,CDCl3):δ190.8,157.6,152.7,
148.9, 142.6,140.2,137.6,134.9,133.4,132.1,130.7,130.0,129.8,129.6, 129.2
(2C),128.9,126.9,126.3,122.4,24.3,14.0；
Embodiment 7
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), 0.3mmol 1- ethyl -3- isonitrile base benzene
The tetrafluoro boric acid copper liquor (22.8mg) of (39.3mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45% are added
Into 15mL heavy wall pressure resistance reaction tube, adds 3mL toluene and make solvent.Then, magnetic agitation 18 hours at 80 DEG C.To gained
Two spoon column chromatography silica gels (1 00-200 mesh) is added in reaction solution, by the progress silica gel column chromatography separation of gained crude product, and with
Volume ratio is that the petroleum ether of 30:1 and the mixture of ethyl acetate are eluted as eluant, eluent, and TLC tracks elution process, collects
Eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is yellow solid, is produced
Rate 26%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.73(s,1H),8.27–8.24(m,2H), 7.94–7.91
(m,1H),7.88–7.85(m,1H),7.77–7.76(m,3H),7.55 –7.50(m,3H),7.25–7.15(m,3H),2.65
(q, J=7.5Hz, 2H), 1.28 (t, J=7.5Hz, 3H)；13C NMR(125MHz,CDCl3):δ190.8,157.6,152.7,
148.9, 142.6,140.2,137.6,134.9,133.4,132.1,130.7,130.0,129.8,129.6, 129.2
(2C),128.9,126.9,126.3,122.4,24.3,14.0；
Embodiment 8
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), 0.3mmol 1- ethyl -3- isonitrile base benzene
The tetrafluoro boric acid copper liquor (22.8mg) of (39.3mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol45% are added
Into 15mL heavy wall pressure resistance reaction tube, adds 3mL nitromethane and make solvent.Then, magnetic agitation 18 hours at 80 DEG C.To
Two spoon column chromatography silica gels (100-200 mesh) is added in gained reaction solution, gained crude product is subjected to silica gel column chromatography separation,
And eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracks elution process,
The eluent containing target product is collected, merges the eluent solvent is evaporated off and obtain target product.The substance is solid for yellow
Body, yield 49%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.73(s,1H),8.27–8.24(m,2H), 7.94–7.91
(m,1H),7.88–7.85(m,1H),7.77–7.76(m,3H),7.55 –7.50(m,3H),7.25–7.15(m,3H),2.65
(q, J=7.5Hz, 2H), 1.28 (t, J=7.5Hz, 3H)；13C NMR(125MHz,CDCl3):δ190.8,157.6,152.7,
148.9, 142.6,140.2,137.6,134.9,133.4,132.1,130.7,130.0,129.8,129.6, 129.2
(2C),128.9,126.9,126.3,122.4,24.3,14.0；
Embodiment 9
By 0.3mmol 3- (3- methoxyphenyl)-quinoxaline -2- formaldehyde (79.2mg), 0.6mmol tert-butyl isonitrile
The tetrafluoro boric acid copper liquor (22.8mg) of (49.8mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45% are added
Into 15mL heavy wall pressure resistance reaction tube, 3mL 1,2- methylene chloride as solvent are added.Then, magnetic agitation 18 is small at 50 DEG C
When.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, gained crude product is subjected to silica gel column chromatography point
From, and eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracking elution
Process collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is Huang
Color solid, yield 59%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.24–8.22(m,2H),7.91–7.87 (m,1H),7.85–
7.82 (m, 1H), 7.40 (t, J=8.0Hz, 1H), 7.31-7.30 (m, 1H), 7.22-7.20 (m, 1H), 7.05-7.02 (m,
1H),6.76(s,1H),3.89(s, 3H),1.26(s,9H)；13C NMR(125MHz,CDCl3):δ191.5,160.2,
159.1,152.3, 149.7,142.3,140.4,139.1,131.8,130.4,130.1,129.7,129.5,121.6,
116.3,114.0,55.4,51.8,28.1；
Embodiment 10
By 0.3mmol 3- (3- methoxyphenyl)-quinoxaline -2- formaldehyde (79.2mg), 0.6mmol tert-butyl isonitrile
The tetrafluoro boric acid copper liquor (22.8mg) of (49.8mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45% are added
Into 15mL heavy wall pressure resistance reaction tube, 3mL 1,2- methylene chloride as solvent are added.Then, magnetic agitation 18 is small at 90 DEG C
When.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, gained crude product is subjected to silica gel column chromatography point
From, and eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracking elution
Process collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is Huang
Color solid, yield 68%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.24–8.22(m,2H),7.91–7.87 (m,1H),7.85–
7.82 (m, 1H), 7.40 (t, J=8.0Hz, 1H), 7.31-7.30 (m, 1H), 7.22-7.20 (m, 1H), 7.05-7.02 (m,
1H),6.76(s,1H),3.89(s, 3H),1.26(s,9H)；13C NMR(125MHz,CDCl3):δ191.5,160.2,
159.1,152.3, 149.7,142.3,140.4,139.1,131.8,130.4,130.1,129.7,129.5,121.6,
116.3,114.0,55.4,51.8,28.1；
Embodiment 11
By 0.3mmol 6,7- dimethyl-3- phenyl-quinoxaline-2- formaldehyde (78.6mg), 1-methoxyl group of 0.3mmol-
The tetrafluoro boric acid copper liquor of 4- isonitrile base benzene (39.9mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45%
(22.8mg) is added in 15mL heavy wall pressure resistance reaction tube, adds 3 mL 1,2- methylene chloride as solvent.Then, in 80 DEG C
Lower magnetic agitation 12 hours.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, by gained crude product into
The separation of row silica gel column chromatography, and washed using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent
De-, TLC tracks elution process, collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target
Product.The substance is yellow solid, yield 50%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.69(s,1H),8.00(s,1H),7.97 (s,1H),7.73–
7.71(m,2H),7.50–7.45(m,5H),6.89–7.86(m, 2H),3.80(s,3H),2.56(s,3H),2.56(s,
3H),；13C NMR(125MHz,CDCl3): δ190.6,157.6,157.2,151.9,147.7,143.2,141.5,141.4,
139.0,137.7, 129.6,129.4,129.1,129.0,128.6,128.5,121.5,114.3,55.5,20.6,20.4；
Embodiment 12
By 0.3mmol 6,7- dimethyl-3- phenyl-quinoxaline-2- formaldehyde (78.6mg), 1-methoxyl group of 0.3mmol-
The tetrafluoro boric acid copper liquor of 4- isonitrile base benzene (39.9mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45%
(22.8mg) is added in 15mL heavy wall pressure resistance reaction tube, adds 3 mL 1,2- methylene chloride as solvent.Then, in 80 DEG C
Lower magnetic agitation 30 hours.Two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, by gained crude product into
The separation of row silica gel column chromatography, and washed using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent
De-, TLC tracks elution process, collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target
Product.The substance is yellow solid, yield 70%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.69(s,1H),8.00(s,1H),7.97 (s,1H),7.73–
7.71(m,2H),7.50–7.45(m,5H),6.89–7.86(m, 2H),3.80(s,3H),2.56(s,3H),2.56(s,
3H),；13C NMR(125MHz,CDCl3): δ190.6,157.6,157.2,151.9,147.7,143.2,141.5,141.4,
139.0,137.7, 129.6,129.4,129.1,129.0,128.6,128.5,121.5,114.3,55.5,20.6,20.4；
Embodiment 13
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), 0.3mmol 1- tert-butyl -4- isonitrile base benzene
The tetrafluoro boric acid copper liquor (22.8mg) of (47.7mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45% are added
Into 15mL heavy wall pressure resistance reaction tube, 3mL 1,2- methylene chloride as solvent are added.Then, magnetic agitation 18 is small at 80 DEG C
When, two spoon column chromatography silica gels (100-200 mesh) is added into gained reaction solution, gained crude product is subjected to silica gel column chromatography point
From, and eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracking elution
Process collects the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is Huang
Color solid, yield 56%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.73(s,1H),8.26–8.23(m,2H), 7.93–7.89
(m,1H),7.87–7.83(m,1H),7.77–7.75(m,2H),7.52 –7.36(m,5H),7.39–7.36(m,2H),1.32
(s,9H)；13C NMR(125MHz, CDCl3):δ190.4,157.5,152.6,148.9,148.7,142.5,140.1,
137.4,133.5, 132.0,130.6,129.9,129.7,129.5,129.10,129.07,126.0,119.7,34.5,
31.3；.
Embodiment 14
By 0.3mmol 3- phenyl-quinoxaline -2- formaldehyde (70.2mg), 0.3mmol 2- isonitrile base -1,3,5- trimethyl
The tetrafluoro boric acid copper liquor of benzene (43.5mg), 0.3mmol selenium dioxide (33.3mg) and 0.03mmol 45% is added to 15mL
In heavy wall pressure resistance reaction tube, 3mL 1,2- methylene chloride as solvent are added.Then, magnetic agitation 18 hours at 80 DEG C, to
Two spoon column chromatography silica gels (100-200 mesh) is added in gained reaction solution, gained crude product is subjected to silica gel column chromatography separation, and
It is eluted using volume ratio for the petroleum ether of 30:1 and the mixture of ethyl acetate as eluant, eluent, TLC tracks elution process, receives
Collect the eluent containing target product, merges the eluent solvent is evaporated off and obtain target product.The substance is yellow solid,
Yield 55%.
Characterize data:1H NMR(500MHz,CDCl3):δ8.25–8.23(m,3H),7.92–7.89 (m,1H),7.87–
7.83(m,1H),7.77–7.75(m,2H),7.55–7.51(m, 3H),6.85(s,2H),2.25(s,3H),2.01(s,
6H),；13C NMR(125MHz,CDCl3): δ190.9,158.0,152.4,149.1,142.4,140.2,137.8,137.6,
134.7,131.9, 130.5,129.9,129.7,129.5,129.2(2C),129.1,129.0,20.9,18.1。
Claims (10)
1. a kind of synthetic method of alpha-keto amide class compound, it is characterised in that: the method specifically carries out as follows:
Isonitrile shown in quinoxaline -2- formaldehyde, formula II shown in formula I is dissolved in organic solvent, in copper catalyst and oxidant
Under the action of, it is reacted 12~30 hours in 50~90 DEG C, gained reaction solution is post-treated to obtain alpha-keto amide class shown in formula III
Compound；The amount of the substance of isonitrile, copper catalyst and oxidant shown in quinoxaline -2- formaldehyde, formula II shown in the formula I
The ratio between be 1:1~2:0.05~0.2:1；The copper catalyst is copper trifluoromethanesulfcomposite or copper tetrafluoroborate, the tetrafluoro
Copper borate is added in form of an aqueous solutions；The oxidant is selenium dioxide, the chloro- 5,6- dicyano -1,4- benzoquinones of 2,3- bis-
Or one of iodic anhydride or more than one mixture；
In formula I or formula III,
R1For CH3, Cl or Br；R2For H, CH3、OCH3, F, Cl, Br or CF3；
n1~n2For the number of substituent group, n1For 1~4, n2It is 1~5；
In formula II,
R3For
2. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: the organic solvent is
One of toluene, 1,2- dichloroethanes, nitromethane or more than one mixed solvent.
3. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: the organic solvent
Additional amount is calculated as 10ml/mmol with the amount of the substance of quinoxaline -2- formaldehyde shown in the formula I.
4. the synthetic method of alpha-keto amide class compound as claimed in claim 2, it is characterised in that: the organic solvent is
1,2- dichloroethanes.
5. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: the oxidant is two
Selenium oxide.
6. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: the n1It is 1 or 2, n2
It is 1.
7. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: shown in the formula I
The ratio between quinoxaline -2- formaldehyde and the amount of substance of copper catalyst are 1:0.1.
8. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: the R3For
When, the ratio between the amount of substance of isonitrile shown in quinoxaline -2- formaldehyde and formula II shown in formula I is 1:2.
9. the synthetic method of the alpha-keto amide class compound as described in one of claim 1~8, it is characterised in that: the reaction
The post-processing approach of liquid are as follows: after reaction, the column chromatography silica gel of 100-200 mesh and vacuum distillation are added into gained reaction solution
Solvent is removed, gained crude product is subjected to silica gel column chromatography separation, and be the petroleum ether and ethyl acetate of 30:1 with volume ratio
Mixture is eluted as eluant, eluent, and TLC tracks elution process, collects the eluent containing target product, is merged described
Eluent is evaporated off solvent and obtains alpha-keto amide class compound shown in formula III.
10. the synthetic method of alpha-keto amide class compound as described in claim 1, it is characterised in that: the method is specific
It carries out as follows:
Using isonitrile shown in quinoxaline -2- formaldehyde, formula II shown in formula I as starting material, it is dissolved in organic solvent, in copper catalyst
Under the action of oxidant, is reacted in 80 DEG C 18 hours, after reaction, the column of 100-200 mesh is added into gained reaction solution
Chromatographic silica gel is simultaneously evaporated under reduced pressure removing solvent, gained crude product is carried out silica gel column chromatography separation, and be 30:1's with volume ratio
The mixture of petroleum ether and ethyl acetate is eluted as eluant, eluent, and TLC tracks elution process, and collection contains target product
Eluent, merges the eluent solvent is evaporated off and obtain alpha-keto amide class compound shown in formula III；Shown in the formula I
The ratio between amount of substance of isonitrile shown in quinoxaline -2- formaldehyde, formula II, copper catalyst and oxidant is 1:1~2:0.1:1；Institute
The copper catalyst stated is the aqueous solution of the copper tetrafluoroborate of 45%wt；The oxidant is selenium dioxide；Described is organic molten
Agent is 1,2- dichloroethanes；The additional amount of the organic solvent is with the substance of quinoxaline -2- formaldehyde shown in the formula I
Amount is calculated as 10ml/mmol.
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| CN109422701A (en) * | 2017-08-25 | 2019-03-05 | 浙江工业大学 | A kind of synthetic method of quinokysalines and its derivative |
| CN109422685A (en) * | 2017-08-25 | 2019-03-05 | 浙江工业大学 | A kind of synthetic method of N- acetyl group phenanthridines -6- amide and its derivative |
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| CN109422701A (en) * | 2017-08-25 | 2019-03-05 | 浙江工业大学 | A kind of synthetic method of quinokysalines and its derivative |
| CN109422685A (en) * | 2017-08-25 | 2019-03-05 | 浙江工业大学 | A kind of synthetic method of N- acetyl group phenanthridines -6- amide and its derivative |
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