CN107098829B - A method of alpha-keto amide is synthesized using micro flow field technology continuous flow - Google Patents
A method of alpha-keto amide is synthesized using micro flow field technology continuous flow Download PDFInfo
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- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
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- C07C231/00—Preparation of carboxylic acid amides
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Abstract
The invention discloses a kind of methods using micro flow field technology continuous flow synthesis alpha-keto amide.It includes the following steps: (1) for α-methylbenzylalcohol, and aminated compounds, acid binding agent, catalyst, 2,2,6,6- tetramethyl piperidine oxides, benzene series solvent is mixed in a certain ratio, and obtains heterogeneous solution；(2) heterogeneous solution obtained in step (1) is pumped into micro-reaction device with oxygen simultaneously while stirring and is reacted, collect efflux after reaction, it is post-treated to obtain alpha-keto amide.The reactor large specific surface area that the present invention utilizes, heat transfer, mass transfer ability are strong, highly-safe；Reaction volume of the invention is small, reaction time is short, rapid reaction, high income；Continuous production can be achieved in the present invention, and equipment, energy loss are low, there is preferable prospects for commercial application.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to a kind of to synthesize α -one acyl using micro flow field technology continuous flow
The method of amine.
Background technique
Alpha-keto amide is the core skeleton structure of many drugs, natural products, in organic synthesis, pharmaceutical synthesis, bioid
, high molecular material, natural products etc. play a significant role.In terms of organic synthesis, alpha-keto amide can be converted into α-
Amino acid, beta-lactam, 'alpha '-hydroxy acids and heterocyclic compound.Amido bond is one of most basic functional group, root in field of medicaments
About contain amido bond in the drug of a quarter according to statistics, therefore alpha-keto amide is of great significance in terms of biological medicine.?
Biochemical field, amido bond are usually expressed as the key structural elements of the peptide bond in protein molecule, it is by two molecules of ammonia
Base acid dehydration.Amido bond links multiple amino acid moleculars as basic structural unit and then generates peptide and protein.
As bioactive substance, alpha-keto amide is also cell factor inhibitors, epoxide hydrolase inhibitors or zymolyte.
In the method for traditional synthesis alpha-keto amide, mantoquita metallic catalyst is largely used.And existing routine
There are insoluble problems in reaction kettle synthetic method, such as reaction starting material is not easy to obtain, reaction condition requirement is harsh, step
It is rapid it is cumbersome it is not easy to operate, yield is not high, time-consuming, not environmentally etc..
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of sides using micro flow field technology continuous flow synthesis alpha-keto amide
Method, with solve reaction step existing for prior art problem it is cumbersome it is not easy to operate, time-consuming, yield is not high, side reaction can not be kept away
The problems such as exempting from.
In order to solve the above technical problems, The technical solution adopted by the invention is as follows:
A kind of 1 method using micro flow field technology continuous flow synthesis alpha-keto amide, includes the following steps:
(1) by α-methylbenzylalcohol class compound (I), aminated compounds (II), acid binding agent, catalyst, 2,2,6,6- tetramethyls
Phenylpiperidines oxide and the mixing of benzene series solvent, obtain heterogeneous solution；
(2) heterogeneous solution obtained in step (1) is pumped into micro-reaction device with oxygen simultaneously while stirring and is carried out
Reaction, collects efflux after reaction, post-treated to obtain alpha-keto amide (III)；
Wherein, R1 be selected from hydrogen atom, methyl, ethyl, halogen, amide, trifluoromethyl, methyl formate base, group-4 ethyl formate,
Cyano or nitro；R2 is selected from methyl, ethyl, halogen, amide, trifluoromethyl, methyl formate base, group-4 ethyl formate, cyano or nitre
Base；The halogen is selected from fluorine, chlorine, bromine or iodine；
Preferred R1Selected from fluorine, bromine, methoxyl group, R2Selected from cyano, bromine, methyl formate base, amide, nitro.
In step (1), the acid binding agent is pyridine；The catalyst can be ferric trichloride, copper bromide, cuprous bromide, vinegar
Sour copper, copper sulphate etc., preferably ferric trichloride, ferric trichloride are cheap；The benzene series solvent is selected from toluene, paraxylene
Or one of chlorobenzene or a variety of, preferably toluene.
In step (1), the molar ratio of the α-methylbenzylalcohol class compound, aminated compounds and acid binding agent is 1:1:1.5
~1:3:2.8；The molar ratio of α-methylbenzylalcohol class compound, catalyst and 2,2,6,6- tetramethyl piperidine oxides is 1:
0.02:0.02~1:0.28:0.26, concentration of the α-methylbenzylalcohol class compound in benzene series solvent are 0.4~0.67mol/L.
In step (2), the purity of the oxygen is 99.999% or more, at 1 atmosphere pressure, the flow velocity of the oxygen is 0.15~
1L/min.In an embodiment of the present invention, oxygen is that commercially available steel cylinder fills high pure oxygen, and purity is 99.999% or more；The oxygen
Flow velocity be 0.15~1L/min, the flow velocity is that gas flowmeter shows flow velocity, the as gas velocity under standard state under 1atm,
If pressure is Natm in reactor, the true flow velocity of gas is about that 1/N shows flow velocity, and because gas there is dissolution and reaction disappears
The case where consuming, heretofore described reaction time are rough time.
In step (2), in the microreactor (5) of micro-reaction device, the heterogeneous solution flow velocity is not less than 10ml/
min.After gas-liquid-solid mixing, the flow velocity of gas-liquid-solid mixture is greater than 25mL/min, the residence time of the reaction be 35s~
2.56min, the temperature of the reaction are 50 DEG C~120 DEG C.
In step (2), the micro-reaction device includes liquid sample feeding device 1, gas sampler 2, liquid preheating plate 3, gas
Body preheats plate 4, microreactor 5, counterbalance valve 6 and receiver 7, and the liquid sample feeding device 1 is connected in series to liquid preheating plate
3, gas sampler 2 is connected in series to gas preheating plate 4, and liquid mixing preheating plate 3 and gas preheating table block 4 are connected in parallel
To microreactor 5, then it is sequentially connected in series counterbalance valve 6 and receiver 7, it is described to be connected as connecting by connecting tube.
The microreactor 5 is healthy and free from worry G1 reactor, and special heart-shaped structure is conducive to heterogeneous reaction；Preferred institute
The main body reaction volume for stating microreactor 5 is 64mL, includes concatenated 8 pieces of micro-reaction plates.
The counterbalance valve 6 is gas-liquid separator back pressure, back pressure ranges 6-14bar.
The internal diameter of the connecting tube is 2~4mm.
The gas sampler 2 includes oxygen bottle 201, pressure reducing valve 202 and the gas flowmeter 203 being connected in series.
The synthetic reaction of alpha-keto amide is completed invention introduces micro-reaction device, and is utilized not used before
Iron salt catalyst.Using miniflow field technology as technical support, using microreactor as reaction member.Unique microchannel design,
Mass transfer rate greatly is increased, improves the mixing efficiency of heterogeneous reaction, to substantially reduce the reaction time.It is independent
Heat exchange layer can accurately control reaction so that the heat exchange rate of unit area is 1000 times or more of common still reaction kettle
Temperature, so as to avoid the generation of other side reactions.The synthesis of alpha-keto amide compound is carried out using micro flow field technology continuous flow,
The flow velocity of reactant can accurately be controlled by feed pump.Also, due to the investment reactant of serialization, and in micro-reaction device
Reaction process enters without air, eliminates and vacuumizes, removes the troublesome operations such as reaction solution, realizes continuous operation.Therefore, originally
It is a very ideal method that inventive technique continuous flow, which synthesizes alpha-keto amide,.
The utility model has the advantages that compared with prior art, the present invention provides a kind of methods of continuous production alpha-keto amide.It utilizes
Micro-reaction device have large specific surface area, heat transfer, mass transfer ability it is strong, time of contact is short, the equal energy of reactant concentration, reaction temperature
Accurate control, while side reaction is preferably minimized；Micro- reaction system is the parallel system in modular structure, can situation according to demand
Increase and decrease port number and replacement module produce to adjust, and have very high operating flexibility.Also, use this method, obtained product
Quality also improves a lot, and yield is up to 80% or more.
Detailed description of the invention
Fig. 1 is the device and flow diagram that microchannel plate of the present invention is answered.Including liquid sample feeding device 1, gas sampling
Device 2, liquid preheating plate 3, gas preheat plate 4, microreactor 5, counterbalance valve 6 and receiver 7, include in gas sampler 2
Oxygen bottle 201, pressure reducing valve 202 and gas flowmeter 203.
Specific embodiment
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
In embodiment, the gas flow rate is that gas flowmeter shows flow velocity.
Embodiment 1:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 11.81g of 0.1mol specification, the p-aminophenyl nitrile of 0.1mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 88%.
Embodiment 2:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 94%.
Embodiment 3:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 35.44g of 0.1mol specification, the p-aminophenyl nitrile of 0.3mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 91%.
Embodiment 4:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 11.86g, 0.15mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 88%.
Embodiment 5:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 22.14g, 0.28mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 90%.
Embodiment 6:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 0.32g, 0.002mol ferric trichloride powder stir into uniform heterogeneous state with blender.To healthy and free from worry reactor
Nitrogen back pressure is passed through to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80
DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 80%.
Embodiment 7:
Weigh 2.82g, the 2,2,6,6 of 0.02mol specification, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 4.54g, 0.028mol ferric trichloride powder stir into uniform heterogeneous state with blender.To healthy and free from worry reactor
Nitrogen back pressure is passed through to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80
DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 94%.
Embodiment 8:
Weigh 0.28g, the 2 of 0.002mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 83%.
Embodiment 9:
Weigh 3.75g, the 2 of 0.026mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 92%.
Embodiment 10:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.15L/min, the reaction time is about 2.56min, i.e. reaction starts
After 2.56min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 85%.
Embodiment 11:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 1L/min, the reaction time is about 35s, i.e., after reaction starts 35s,
Reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the conversion of the alpha-keto amide class product of generation
Rate is 80%.
Embodiment 12:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 50 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 81%.
Embodiment 13:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 23.62g of 0.1mol specification, the p-aminophenyl nitrile of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 120
DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 90%.
Embodiment 14:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 34.4g of 0.1mol specification, 4- bromaniline, the 15.82g of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 0.2mol.Determine to be added in liquid to above-mentioned
1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.Nitrogen is passed through to healthy and free from worry reactor
Back pressure switches to oxygen to 10bar, and heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C, it is heterogeneous
Solution flow velocity be 10ml/min, gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e., reaction start 1.1min it
Afterwards, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide class product of generation
Conversion ratio is 83%.
Embodiment 15:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 30.23g of 0.1mol specification, the 4-aminobenzoic acid methyl esters of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 87%.
Embodiment 16:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 27.23g of 0.1mol specification, the Para Amino Benzamide of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 91%.
Embodiment 17:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 27.62g of 0.1mol specification, the 3- nitroaniline of 0.2mol specification,
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 88%.
Embodiment 18:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 14.01g is weighed, 1- (4- fluorophenyl) -1- ethyl alcohol, 23.62g of 0.1mol specification, the p-aminophenyl of 0.2mol specification
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in nitrile, 15.82g, the pyridine of 0.2mol.Liquid is determined to above-mentioned
1.62g is added in body, 0.01mol ferric trichloride powder stirs into uniform heterogeneous state with blender.To healthy and free from worry reactor
Nitrogen back pressure is passed through to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80
DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 94%.
Embodiment 19:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 20.1g is weighed, 1- (4- bromophenyl) -1- ethyl alcohol, 23.62g of 0.1mol specification, the p-aminophenyl of 0.2mol specification
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in nitrile, 15.82g, the pyridine of 0.2mol.Liquid is determined to above-mentioned
1.62g is added in body, 0.01mol ferric trichloride powder stirs into uniform heterogeneous state with blender.To healthy and free from worry reactor
Nitrogen back pressure is passed through to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80
DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 90%.
Embodiment 20:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then weigh 15.21g, 1- (4- methoxyphenyl) -1- ethyl alcohol, 23.62g of 0.1mol specification, 0.2mol specification to ammonia
Toluene solvant is added by total volume constant volume to 200ml in above-mentioned solvent in base cyanophenyl, 15.82g, the pyridine of 0.2mol.To above-mentioned
Determine that 1.62g is added in liquid, 0.01mol ferric trichloride powder, stirs into uniform heterogeneous state with blender.To healthy and free from worry anti-
It answers device to be passed through nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is kept
At 80 DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, that is, is reacted
After starting 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the α -one of generation
The conversion ratio of amides product is 87%.
Embodiment 21:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6, it is molten that-tetramethyl piperidine oxides are completely dissolved in 50ml toluene
In agent, then 12.21g is weighed, α-methylbenzylalcohol, the 11.81g of 0.1mol specification, the p-aminophenyl nitrile of 0.1mol specification,
Toluene solvant is added by total volume constant volume to 250ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.Liquid is determined to above-mentioned
Middle addition 1.62g, 0.01mol ferric trichloride powder stir into uniform heterogeneous state with blender.It is logical to healthy and free from worry reactor
Enter nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at 80 DEG C,
Heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction starts
After 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the alpha-keto amide of generation
The conversion ratio of class product is 85%.
Embodiment 22:
Weigh 2.82g, the 2 of 0.02mol specification, 2,6,6 ,-tetramethyl piperidine oxides are completely dissolved in 50ml to diformazan
In benzene solvent, then 12.21g is weighed, α-methylbenzylalcohol, the 11.81g of 0.1mol specification, the p-aminophenyl nitrile of 0.1mol specification,
Paraxylene solvent is added by total volume constant volume to 150ml in above-mentioned solvent in the pyridine of 15.82g, 0.2mol.To above-mentioned fixed
1.62g is added in liquid, 0.01mol ferric trichloride powder stirs into uniform heterogeneous state with blender.To healthy and free from worry reaction
Device is passed through nitrogen back pressure to 10bar, switches to oxygen, heterogeneous solution is pumped into reactor simultaneously.Reaction temperature is maintained at
80 DEG C, heterogeneous solution flow velocity is 10ml/min, and gas flow rate 0.5L/min, the reaction time is about 1.1min, i.e. reaction is opened
After beginning 1.1min, reaction solution is collected in receiving flask.Through efficient liquid phase chromatographic analysis, in this secondary response, the α -one acyl of generation
The conversion ratio of amine product is 83%.
Claims (9)
1. a kind of method using micro flow field technology continuous flow synthesis alpha-keto amide, which comprises the steps of:
(1) by α-methylbenzylalcohol class compound (I), aminated compounds (II), acid binding agent, catalyst, 2,2,6,6- tetramethyl piperazines
Pyridine oxide and the mixing of benzene series solvent, obtain heterogeneous solution；
(2) heterogeneous solution obtained in step (1) is pumped into micro-reaction device with oxygen simultaneously while stirring, is carried out anti-
It answers, collects efflux after reaction, it is post-treated to obtain alpha-keto amide (III)；
Wherein, R1 is selected from hydrogen atom, methyl, ethyl, halogen, amide, trifluoromethyl, methyl formate base, group-4 ethyl formate, cyano
Or nitro；R2 is selected from methyl, ethyl, halogen, amide, trifluoromethyl, methyl formate base, group-4 ethyl formate, cyano or nitro；Institute
It states halogen and is selected from fluorine, chlorine, bromine or iodine；
In step (1), the acid binding agent is pyridine；The catalyst is ferric trichloride, and the benzene series solvent is selected from toluene, to two
One of toluene or chlorobenzene are a variety of.
2. the method according to claim 1, wherein in step (1), the α-methylbenzylalcohol class compound, amine
The molar ratio of class compound and acid binding agent is 1: 1: 1.5~1: 3: 2.8；α-methylbenzylalcohol class compound, catalyst and 2,2,6,
The molar ratio of 6- tetramethyl piperidine oxides is 1: 0.02: 0.02~1: 0.28: 0.26；α-methylbenzylalcohol class compound is in benzene series
Concentration in solvent is 0.4~0.67mol/L.
3. the method according to claim 1, wherein in step (2), the purity of the oxygen 99.999% with
On, at 1 atmosphere pressure, the flow velocity of the oxygen is 0.15~1L/min.
4. the method according to claim 1, wherein in step (2), in the microreactor (5) of micro-reaction device
In, the heterogeneous solution flow velocity is not less than 10ml/min, and the residence time of the reaction is 35s~2.56min, the reaction
Temperature be 50 DEG C~120 DEG C.
5. the method according to claim 1, wherein the micro-reaction device includes Liquid sample introduction in step (2)
Device (1), gas sampler (2), liquid preheating plate (3), gas preheat plate (4), microreactor (5), counterbalance valve (6) and connect
It receives device (7), the liquid sample feeding device (1) is connected in series to liquid preheating plate (3), and gas sampler (2) is connected in series to gas
Body preheats plate (4), and liquid preheating plate (3) and gas preheating table block (4) are parallel-connected to microreactor (5), then successively go here and there
Connection is connected to counterbalance valve (6) and receiver (7), described to be connected as connecting by connecting tube.
6. according to the method described in claim 5, it is characterized in that, the microreactor (5) is healthy and free from worry G1 reactor.
7. according to the method described in claim 5, it is characterized in that, the counterbalance valve (6) is gas-liquid separator back pressure, back pressure model
It encloses for 6-14bar.
8. according to the method described in claim 5, it is characterized in that, the internal diameter of the connecting tube is 2~4mm.
9. according to the method described in claim 5, it is characterized in that, the gas sampler (2) includes the oxygen being connected in series
Steel cylinder (201), pressure reducing valve (202) and gas flowmeter (203).
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