Technical background: phenoxy acetic acid ester is a very important compound of class, they are widely used in medicine and pesticide.Example
As, CN102718727 discloses the phenoxy acetic acid ester type compound containing urea groups and can not only be used for the activator of glucokinase,
Again can be as the activated receptor activator of peroxidase paraphyte.CN102532058 discloses containing benzo [1,2,3] thiadiazoles-7-
The phenoxy acetic acid ester type compound of carboxylic acid ester groups can be as Plant activator.It addition, 2-(5-fluoro-2,4-2,4-dinitrophenoxy)
Acetas is also the important intermediate of synthesis N-phenyl phthalmide herbicide flumioxazin.
The method of synthesis phenoxy acetic acid ester type compound generally has two kinds.The first is based on phenol compound and halogenated acetic acids
The nucleophilic substitution of ester, the second is aromatic nucleophilic substitution reaction based on halogenated aryl hydrocarbon Yu hydroxyacetic acid ester type compound.
There is nucleophilic substitution with monoxone in such as G.C.Finger report 3-fluorophenol under sodium hydroxide effect, generates 3-
Fluorobenzene fluoroacetic acid, yield is 73%.Then 3-fluorobenzene fluoroacetic acid nitrification obtains 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid, yield
It is 30%.(J.Am.Chem.Soc,1959,81,1,94-101).Although this method can prepare 2-(5-fluoro-2,4-2,4-dinitrophenoxy)
Acetic acid, but raw material 3-fluorophenol used is costly, and gross production rate is low.
EP0415641 discloses with 5-fluoro-2-nitrophenol as initiation material, sends out with methyl bromoacetate under the effect of potassium carbonate
Raw nucleophilic substitution, yield is 93%.Then the further nitrification of 5-fluoro-2-nitrophenoxyacetic acid ester generates 2-(the fluoro-2,4-of 5-bis-
Nitrobenzol oxygen) methyl acetate, yield is 98%.Although this method overall yield is higher, but it is the use of the 5-fluoro-2-nitre of costliness
Base phenol, another kind of raw material methyl bromoacetate has strong impulse effect to eyes, skin, mucosa and respiratory tract, the most also
It is unfavorable for industrialized production.
JP1989075452 and EP0237899 discloses the synthetic method of another kind of 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetas.
The method is with 1, and 5-bis-chloro-2,4-dinitro benzene is initiation material, first with glycolic acid esters in potassium carbonate, crown ether and acetonitrile system
Back flow reaction, generates 2-(5-chloro-2,4-2,4-dinitrophenoxy) acetas, and yield is 73.9%.2-(the 5-chloro-2,4-dinitro obtained
Benzene oxygen) acetas carries out fluorination reaction again in DMSO with potassium fluoride, generates 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetas,
Yield is 89.9%.The method successfully make use of the sucting electronic effect of dinitro on phenyl ring, enables aromatic nucleophilic substitution reaction
Carry out.But the glycolic acid esters of the method use costliness is as raw material, simultaneously because chlorinated aromatic hydrocarbons activity is the highest, so the first step
Productivity is not ideal enough.In addition in order to obtain 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetas, further fluorination reaction is needed.This fluorine
Change reaction and consersion unit is required higher, produce the sulfur-bearing three wastes, be unfavorable for industrialized production.
JP1992305556 also discloses with 1,5-bis-fluoro-2, and 4-dinitro benzene is raw material, with Butyl Glycolate at potassium carbonate and
There is aromatic nucleophilic substitution reaction under the effect of the triethylamine of catalytic amount, generate 2-(5-fluoro-2,4-2,4-dinitrophenoxy) butyl acetate,
Yield is 92%.This solves the problem that chlorinated aromatic hydrocarbons and glycolic acid esters reaction yield are the highest, but used
Raw material hydroxyl butyl acetate is expensive.
EP0237899 also discloses with 1,5-bis-fluoro-2, and 4-dinitro benzene and hydroxyacetic acid are raw material, and fragrance occurs under alkali effect
Nucleophilic substitution, generates 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid.But concrete reactions steps and yield are the openest.
CN101948389 uses same process, with 1,5-bis-fluoro-2 subsequently, and 4-dinitro benzene and hydroxyacetic acid are raw material,
Under alkali effect, reaction generates 2-(5-fluoro-2,4-2,4-dinitrophenoxy) acetic acid, and yield is between 28-81%.Due to the fluoro-2,4-of 1,5-bis-
Dinitro benzene is the most active, if there is any water in reaction system, water can occur competition anti-with hydroxyacetic acid
Should, first hydrolysis produces nitrophenol by-product, and this by-product causes catalyst poisoning in hydrogenation reaction subsequently.Therefore,
This technique needs strictly to control raw material, alkali and the moisture of whole system.Raw material hydroxyl acetic acid the easiest deliquescence, and
And high temperature easily decomposes when removing water.All of these factors taken together causes the method to be unfavorable for industrialized production.
Summary of the invention
An object of the present invention is to overcome the existing deficiency preparing phenoxy acetic acid intermediate technology, from cheap and easily-available hydroxyl second
Aqueous acid and organic amine set out, and are dehydrated into salt, then react with halogenated aryl hydrocarbon, synthesize phenoxy acetic acid.This invention not only solves
The problem that anhydrous hydroxyacetic acid cost is high, is effectively controlled the moisture in reaction system simultaneously.The most not only
Inhibit and produce in aromatic nucleophilic substitution reaction hydrolysising by-product nitrophenol, improve reaction yield simultaneously.The present invention's
Another purpose is to develop the more effective synthetic method of phenoxy acetic acid ester on the basis of new technology prepared by phenoxy acetic acid further.
The synthetic method of a kind of phenoxy acetic acid ester (I), it is characterised in that the formula of compound (I) is as follows:
In formula:
R1For C1-C12Alkyl;
R2For H, methyl or phenyl;
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
Described synthetic method comprises the steps:
Step (a): compound (II) and compound (III) react to obtain compound (IV) in organic solvent;
The formula of compound (II) is as follows:
In formula:
R2For H, methyl or phenyl;
The formula of compound (III) is as follows:
In formula:
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
The formula of compound (IV) is as follows:
In formula:
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Step (b): compound (IV) and compound (V) obtain compound (VI) under acid binding agent effect,
The formula of compound (V) is as follows:
In formula:
X is F, Cl, Br or I;
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
The formula of compound (VI) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Step (c): compound (VI) and compound (VII) direct reaction are prepared into compound (I);
The formula of compound (VII) is as follows:
R1-L(VII)
In formula:
R1For C1-C12Alkyl;
L is Cl, Br, I, MeSO3 -, R1OCO2 -, TsSO3 -Or R1OSO3 -, wherein R1It is as defined above.
In step (a), described solvent is selected from toluene, dimethylbenzene, dichloromethane, chloroform, methanol, ethanol or isopropyl
One or more in alcohol;Compound (II) is 1:1-1:5 with the molar ratio of compound (III);Reaction temperature is from-30 DEG C-50 DEG C;
In step (b), described acid binding agent is inorganic base or organic base;Inorganic base selected from sodium carbonate, potassium carbonate, potassium hydroxide or
Sodium hydroxide;Organic base is selected from triethylamine, tripropyl amine (TPA), tri-n-butylamine, diethylamine, hexanamine, piperidines, pyridine or compound
(III) own;Compound (V) is 1:0.9-1:5 with the molar ratio of compound (IV);Acid binding agent and the mol ratio of compound (IV)
Example is 1:1-5:1;Reaction temperature is from-30 DEG C-25 DEG C;Compound (VI) is 1:0.9-1:5 with the molar ratio of compound (VII);
Reaction temperature is from-30 DEG C-50 DEG C.
In step (a), described solvent is preferably toluene and dichloromethane;Compound (II) is preferred with the molar ratio of compound (III)
For 1:1-1:2;Reaction temperature is preferably from 0-25 DEG C;In step (b), described acid binding agent is preferably triethylamine;Compound
(V) molar ratio with compound (IV) is preferably 1:0.9-1:1.2;Acid binding agent is preferably with the molar ratio of compound (IV)
1:1-1.2:1;Reaction temperature is preferably from-5-10 DEG C.Compound (VI) is preferably 1:0.9-1:2 with the molar ratio of compound (VII);
Reaction temperature is preferably from-5 DEG C-25 DEG C.
The synthetic method of a kind of phenoxy acetic acid ester (I), it is characterised in that the formula of compound (I) is as follows:
In formula:
R1For C1-C12Alkyl;
R2For H, methyl or phenyl;
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
Described synthetic method includes:
Step (a): compound (II) and compound (III) react to obtain compound (IV) in organic solvent,
The formula of compound (II) is as follows:
In formula:
R2For H, methyl or phenyl;
The formula of compound (III) is as follows:
In formula:
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
The formula of compound (IV) is as follows:
In formula:
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Step (b): compound (IV) and compound (V) obtain compound (VI) under acid binding agent effect,
The formula of compound (V) is as follows:
In formula:
X is F, Cl, Br or I;
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
The formula of compound (VI) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Step (c '): compound (VI) is free under mineral acid effect obtains compound (VIII), and the formula of compound (VIII) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
Step (d): compound (VIII) and compound (IX) reacts under acid catalysis and be prepared into compound (I), or compound (VIII) and change
Compound (VII) reacts under alkali effect and is prepared into compound (I),
The formula of compound (IX) is as follows:
R1OH(IX)
In formula:
R1For C1-C12Alkyl;
The formula of compound (VII) is as follows:
R1-L(VII)
In formula:
R1For C1-C12Alkyl;
L is Cl, Br, I, MeSO3 -, R1OCO2 -, TsSO3 -Or R1OSO3 -, wherein R1It is as defined above.
In step (a), described solvent is selected from toluene, dimethylbenzene, dichloromethane, chloroform, methanol, ethanol or isopropyl
One or more in alcohol;Compound (II) is 1:1-1:5 with the molar ratio of compound (III);Reaction temperature is from-30 DEG C-50 DEG C;
In step (b), described acid binding agent is inorganic base or organic base;Inorganic base selected from sodium carbonate, potassium carbonate, potassium hydroxide or
Sodium hydroxide;Organic base is selected from triethylamine, tripropyl amine (TPA), tri-n-butylamine, diethylamine, hexanamine, piperidines, pyridine or compound
(III) own;Compound (V) is 1:0.9-1:5 with the molar ratio of compound (IV);Acid binding agent and the mol ratio of compound (IV)
Example is 1:1-5:1;Reaction temperature is from-30 DEG C-25 DEG C;In step (c '), described mineral acid is selected from sulphuric acid, hydrochloric acid or phosphorus
Acid;Mineral acid is 1:1-15:1 with the molar ratio of compound (IV);Reaction temperature is from-30 DEG C-25 DEG C;In step (d),
Described acid catalyst is selected from sulphuric acid, hydrochloric acid, acetic acid, phosphoric acid or p-methyl benzenesulfonic acid;Alkali is inorganic base or organic base;Inorganic base
Selected from sodium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide;Organic base is selected from triethylamine, piperidines, DBU or pyridine;Change
Compound (VIII) is 1:0.9-1:5 with the molar ratio of compound (IX) or compound (VII);Acid or alkali and compound (IV) rub
Your ratio is 1:1-5:1;Reaction temperature is from-30 DEG C-130 DEG C.
In step (a), described solvent is preferably toluene or dichloromethane;Compound (II) is preferred with the molar ratio of compound (III)
For 1:1-1:2;Reaction temperature is preferably from 0-25 DEG C;In step (b), described acid binding agent is preferably triethylamine;Compound
(V) molar ratio with compound (IV) is preferably 1:0.9-1:1.2;Acid binding agent is preferably with the molar ratio of compound (IV)
1:1-1.2:1;Reaction temperature is preferably from-5-10 DEG C;In step (c '), described mineral acid is preferably hydrochloric acid;Mineral acid with
The molar ratio of compound (IV) is preferably 1:1-2:1;Reaction temperature is preferably from-5-25 DEG C;In step (d), described
Acid catalyst is preferably sulphuric acid;Alkali is inorganic base or organic base;Inorganic base is preferably potassium hydroxide;Organic base is preferably triethylamine;
Compound (VIII) is preferably 1:0.9-1:2 with the molar ratio of compound (IX) or compound (VII);Acid or alkali and compound (IV)
Molar ratio be preferably 1:0.9-1:2;Reaction temperature is preferably from-5-130 DEG C.
A kind of phenoxy acetic acid ammonium salt (VI), it is characterised in that the formula of compound (VI) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
The synthetic method of a kind of phenoxy acetic acid ammonium salt (VI), it is characterised in that the formula of compound (VI) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Described method includes:
Step (a): compound (II) and compound (III) obtain compound (IV) in organic solvent,
The formula of compound (II) is as follows:
In formula:
R2For H, methyl or phenyl;
The formula of compound (III) is as follows:
In formula:
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
The formula of compound (IV) is as follows:
In formula:
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Step (b): compound (IV) and compound (V) obtain compound (VI) under acid binding agent effect,
The formula of compound (V) is as follows:
In formula:
X is F, Cl, Br or I;
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN.
In step (a), described solvent is selected from toluene, dimethylbenzene, dichloromethane, chloroform, methanol, ethanol or isopropyl
One or more in alcohol;Compound (II) is 1:1-1:5 with the molar ratio of compound (III);Reaction temperature is from-30 DEG C-50 DEG C;
In step (b), described acid binding agent is inorganic base or organic base;Inorganic base selected from sodium carbonate, potassium carbonate, potassium hydroxide or
Sodium hydroxide;Organic base is selected from triethylamine, tripropyl amine (TPA), tri-n-butylamine, diethylamine, hexanamine, piperidines, pyridine or compound
(III) own;Compound (V) is 1:0.9-1:5 with the molar ratio of compound (IV);Acid binding agent and the mol ratio of compound (IV)
Example is 1:1-5:1;Reaction temperature is from-30 DEG C-25 DEG C.
In step (a), described solvent is preferably toluene or dichloromethane;Compound (II) is preferred with the molar ratio of compound (III)
For 1:1-1:2;Reaction temperature is preferably from 0-25 DEG C;In step (b), described acid binding agent is preferably triethylamine;Compound
(V) molar ratio with compound (IV) is preferably 1:0.9-1:1.2;Acid binding agent is preferably with the molar ratio of compound (IV)
1:1-1.2:1;Reaction temperature is preferably from-5-10 DEG C.
The synthetic method of a kind of phenoxy acetic acid ammonium salt (VI), it is characterised in that the formula of compound (VI) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ;
Described synthetic method is:
Compound (VIII) and compound (III) obtain compound (VI) in organic solvent,
The formula of compound (VIII) is as follows:
In formula:
Y is H, C1-C4Alkyl, phenyl, F, Cl, Br, NO2, CF3Or CN;
EWG is NO2, CF3Or CN;
R2For H, methyl or phenyl;
The formula of compound (III) is as follows:
In formula:
R3、R4And R5For H, C1-C5Alkyl or C3-C7Cycloalkyl, R3、R4And R5For identical or differ.