CN108689874A - A kind of method and its application preparing 2- aryl malonamides - Google Patents
A kind of method and its application preparing 2- aryl malonamides Download PDFInfo
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- CN108689874A CN108689874A CN201710223444.5A CN201710223444A CN108689874A CN 108689874 A CN108689874 A CN 108689874A CN 201710223444 A CN201710223444 A CN 201710223444A CN 108689874 A CN108689874 A CN 108689874A
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- aryl
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- malonamides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Abstract
The present invention provides a kind of method and its application preparing 2- aryl malonamides.This method is using 2- (cyclohexadienylidene) malononitrile as raw material, and generation one step of aromatisation-hydrolysis obtains 2- aryl malonamides under the action of oxidant and water.Compared with prior art, the method provided by the invention for preparing 2- aryl malonamides has following significant feature and advantage:(1) entirely different synthesis strategy;(2) raw material is simple and easy to get;(3) high income, while avoiding using expensive metallic catalyst, at low cost, suitable industrialized production etc..
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a kind of preparation method and applications of 2- aryl malonamide.
Background technology
2- aryl malonamide compounds are a kind of important organic synthesis intermediates.Such as 2- (2,6- diethyl -4- first
Base phenyl) malonamide is the important intermediate (WO000/78881, WO 00/78712) for preparing highy potent herbicide pinoxaden.
The method of synthesis 2- aryl malonamide compounds mainly passes through 2- aryl malononitrile class compound hydrolysis at present
To prepare (WO 00/78712).This method has that raw material 2- aryl malononitrile derivatives are difficult to prepare, especially empty
Between big 2- (2,6- disubstituted aryls) the malononitrile raw material of steric hindrance preparation.It is best to synthesize 2- (2,6- disubstituted aryls) malononitrile
Method be using corresponding aromatic amine compounds be raw material, successively pass through diazotising-halogenated (Sandmeyer) reaction, C-C gold
Belong to catalyzed coupling reaction to prepare (WO 2004/050607).In order to make metal catalyzed coupling reaction have ideal yield, diazonium
Halogenating agent used in change-halogenating reaction must be valuable bromine or iodine compound.It is more than during diazotising-halogenating reaction
A large amount of three-waste pollution is generated, there is also security risks and halogen etching problem.In addition to this, the big virtue of the steric hindrance of gained
The C-C metal catalyzed coupling reactions of base halides and malonate derivative are needed using expensive organo-metallic catalyst, catalysis
Agent is of high cost, and is difficult to recycle.
Invention technician in view of the deficiencies of the prior art, by largely thinking deeply and experimental exploring, is surprised to find 2-
Aryl malonamide compounds can be used as raw material by 2- (cyclohexadienylidene) malononitrile and directly prepare.
Invention content
The present invention provides a kind of new methods preparing 2- aryl propane diamide compounds.Specifically, 2- (sub- cyclohexene
Base) one step of aromatisation-hydrolysis occurs under the action of oxidant and water and obtains 2- aryl malonamides malononitrile, with reaction
Formula indicates as follows:
Wherein, R1,R2,R3,R4,R5It is hydrogen, C1-C10 alkyl, C6-C12 aryl independently of one another or contains one or two
Heteroaryl selected from nitrogen, oxygen, sulphur atom.
The oxidant is peroxide, oxygen, air, oxidizing acid.Preferably hydrogen peroxide, potassium peroxydisulfate, dense sulphur
Acid.The molar ratio of oxidant and compound 1 is 0.5-2.0:1, preferably 1.0-1.2:1.
Aromatisation-the hydrolysising reacting temperature is 0-100 DEG C, preferably 60-80 DEG C.
Aromatisation-the hydrolysis carries out under the action of an acid, preferably the concentrated sulfuric acid.
Compared with prior art, the method provided by the invention for preparing 2- aryl malonamides has following significant special
It seeks peace advantage:
(1) entirely different synthesis strategy;
(2) raw material is simple and easy to get;
(3) high income, while avoiding using expensive metallic catalyst, at low cost, suitable industrialized production etc..
Specific implementation mode
The following examples further illustrate some features of the present invention, but the present invention applies for the content of protection
It is not limited by following embodiments with range.
Raw material used in the present invention can be by passing through Knoevenagel condensation reaction systems by cyclonene and malononitrile
Standby (J.Mol.Cata.A.Chem.2003,195 (1-2), 263).
Embodiment one:The preparation of 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide
By raw material 2- (2,6- diethyl -4- methyl -2- alkene -1- cyclohexylidenes) malononitrile 43.0g (0.20mol), over cure
Sour potassium 54.1g (0.2mol) and water 5.4g (0.30mol) are cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise into reaction system.Drip off heating
It is reacted to 70 DEG C.After the reaction was complete, reaction solution is poured into ice water by cooling, and ethyl acetate is extracted twice, and merges organic phase, is done
Dry, condensing crystallizing obtains 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide 40.0g, yield 80%.1H NMR(MeOD,
500MHz):δ 6.99 (s, 2H), 4.81 (s, 1H), 2.60 (q, J=9.0Hz, 4H), 2.32 (s, 3H), 1.22 (t, J=
9.0Hz,6H)。13C NMR(CDCl3,125MHz):δ174.7,145.0,139.0,130.2,128.9,48.9,27.5,21.2,
15.5。
Embodiment two:The preparation of 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide
By raw material 2- (2,6- diethyl -4- methyl -2- alkene -1- cyclohexylidenes) malononitrile 21.4g (0.10mol), 30%
Hydrogen peroxide 13.6g (0.12mol) is cooled to 0-5 DEG C.It drips off and is warming up to 60 DEG C of DEG C of reactions.After the reaction was complete, cooling, by reaction solution
It is poured into ice water, ethyl acetate is extracted twice, and merges organic phase, and dry, condensing crystallizing obtains 2- (2,6- diethyl -4- methyl
Phenyl) malonamide 10.2g.
Embodiment three:The preparation of 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide
By raw material 2- (2,6- diethyl -4- methyl -2- alkene -1- cyclohexylidenes) malononitrile 32.1g (0.15mol), water
6.7g (0.30mol) is cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise into reaction system.It drips off and is warming up to 80 DEG C of reactions.The reaction was complete
Afterwards, cool down, reaction solution be poured into ice water, ethyl acetate is extracted twice, and merges organic phase, dry, condensing crystallizing obtain 2- (2,
6- diethyl -4- aminomethyl phenyls) malonamide 32.7g, yield 88%.
Example IV:The preparation of 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide
By raw material 2- (2,6- diethyl -4- methyl -2- alkene -1- cyclohexylidenes) malononitrile 214.3g (1.00mol), water
27.0g (1.50mol) is cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise into reaction system, while leading to oxygen into reaction system.It drips off
It is warming up to 80 DEG C of reactions.After the reaction was complete, reaction solution is poured into ice water by cooling, and ethyl acetate is extracted twice, and is merged organic
Phase, dry, condensing crystallizing obtains 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide 136.6g.
Embodiment five:The preparation of 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide
By raw material 2- (3- methyl -2- alkene -1- cyclohexylidenes) malononitrile 15.0g (0.09mol), potassium peroxydisulfate 25.7g
(0.09mol) and water 2.6g (0.14mol) are cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise into reaction system.It drips off and is warming up to 70 DEG C instead
It answers.After the reaction was complete, reaction solution is poured into ice water by cooling, and ethyl acetate is extracted twice, and merges organic phase, dry, concentration knot
Crystalline substance obtains 2- (3- aminomethyl phenyls) malonamide 16.2g, yield 89%.
Embodiment six:The preparation of 2- (2,6- diphenyl -4- aminomethyl phenyls) malonamide
By raw material 2- (2,6- diphenyl -4- methyl -2- alkene -1- cyclohexylidenes) malononitrile 31.0g (0.10mol), over cure
Sour potassium 27.0g (0.10mol) and water 2.7g (0.15mol) are cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise into reaction system.Drip off liter
Temperature is reacted to 70 DEG C.After the reaction was complete, reaction solution is poured into ice water by cooling, and ethyl acetate is extracted twice, and merges organic phase,
Dry, condensing crystallizing obtains 2- (2,6- diphenyl -4- aminomethyl phenyls) malonamide 19.6g.1H NMR(MeOD,500MHz):δ
7.50-7.40(m,10H),7.20(s,2H),5.11(s,1H),2.44(s,3H)。
Embodiment seven:The preparation of pinoxaden
By 2- (2,6- diethyl -4- aminomethyl phenyls) malonamide 12.4g (0.05mol) ,s [1,4,5]Oxygen diazacyclo
Heptane nicotinium dihydrochloride 10.5g (0.06mol) and triethylamine 20.2g (0.20mol) are stirred at reflux reaction in dimethylbenzene.It waits for anti-
After answering completely, pivalyl chloride 10.8g (0.09mol), room temperature reaction is added in cooling.After complete reaction, by the mixture with dilute
Salt acid for adjusting pH is acidity, ethyl acetate extraction.Combined organic phase drying, condensing crystallizing obtain product pinoxaden 14.4g,
Yield is 72%.1H NMR(CDCl3,500MHz,TMS):δ8.88(s,2H),4.28-4.26(m,2H),3.94-3.93(m,
2H), 3.89-3.83 (m, 4H), 2.56-2.47 (m, 2H), 2.45-2.40 (m, 2H), 2.39 (s, 3H), 1.12 (t, J=
9.0Hz,3H),1.23(s,9H)。
Claims (10)
1. a kind of preparation method of 2- aryl malonamide, which is characterized in that compound 1 occurs under the action of oxidant and water
One step of aromatisation-hydrolysis obtains 2- aryl malonamide 2, indicates as follows with reaction equation:
Wherein, R1,R2,R3,R4,R5It is hydrogen, C1-C10 alkyl, C6-C12 aryl independently of one another or is selected from containing one or two
The heteroaryl of nitrogen, oxygen, sulphur atom.
2. according to the method described in claim 1, it is characterized in that, R1,R2For C1-C3 alkyl, C6-C12 aryl, R3For C1-C3
Alkyl, R4,R5For hydrogen.
3. according to the method described in claim 2, it is characterized in that, R1,R2For ethyl, R3For methyl.
4. according to the method described in claim 1, it is characterized in that, the oxidant is peroxide, oxygen, air, oxygen
The property changed acid;The molar ratio of oxidant and compound 1 is 0.5-2.0:1.
5. according to the method described in claim 4, it is characterized in that, the oxidant is preferably potassium peroxydisulfate, the concentrated sulfuric acid;Oxygen
The molar ratio of agent and compound 1 is preferably 1.0-1.2:1.
6. according to the method described in claim 1, it is characterized in that, reaction temperature is 0-100 DEG C.
7. according to the method described in claim 6, it is characterized in that, reaction temperature is preferably 60-80 DEG C.
8. according to right 1-6 any one of them methods, which is characterized in that the reaction carries out under the action of an acid.
9. method according to claim 8, which is characterized in that the acid is preferably the concentrated sulfuric acid.
10. application of the claim 1-9 any one of them method in pinoxaden synthesis.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111372913A (en) * | 2019-04-01 | 2020-07-03 | 泸州东方农化有限公司 | Method for preparing 2-aryl malonic acid derivative, intermediate and application thereof |
| CN113968798A (en) * | 2020-07-24 | 2022-01-25 | 沈阳中化农药化工研发有限公司 | Cyclohexyl ester compound, preparation method and application thereof |
| US11970507B2 (en) | 2021-09-29 | 2024-04-30 | Oriental (Luzhou) Agrochemicals Co., Ltd. | Method for preparing 2-arylmalonic acid derivative and intermediate, and use thereof |
Citations (2)
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| US4169108A (en) * | 1973-08-16 | 1979-09-25 | Sterling Drug Inc. | 5(OR 6)-[(Substituted-amino)alkyl]-2,3-naphthalenediols |
| US4327022A (en) * | 1973-08-16 | 1982-04-27 | Sterling Drug Inc. | Heterocyclic alkyl naphthols |
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2017
- 2017-04-07 CN CN201710223444.5A patent/CN108689874B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4169108A (en) * | 1973-08-16 | 1979-09-25 | Sterling Drug Inc. | 5(OR 6)-[(Substituted-amino)alkyl]-2,3-naphthalenediols |
| US4327022A (en) * | 1973-08-16 | 1982-04-27 | Sterling Drug Inc. | Heterocyclic alkyl naphthols |
Non-Patent Citations (1)
| Title |
|---|
| G.GURUNADHAM等: "A simple and Efficient Procedure for synthesis of agomelatine", 《ASIAN JOURNAL OF CHEMISTRY》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111372913A (en) * | 2019-04-01 | 2020-07-03 | 泸州东方农化有限公司 | Method for preparing 2-aryl malonic acid derivative, intermediate and application thereof |
| WO2020199081A1 (en) * | 2019-04-01 | 2020-10-08 | 泸州东方农化有限公司 | Method for preparing 2-arylmalonic acid derivative, intermediate, and application thereof |
| CN111372913B (en) * | 2019-04-01 | 2021-09-03 | 泸州东方农化有限公司 | Method for preparing 2-aryl malonic acid derivative, intermediate and application thereof |
| AU2019439692B2 (en) * | 2019-04-01 | 2023-01-12 | Oriental (Luzhou) Agrochemicals Co., Ltd. | Method for preparing 2-arylmalonic acid derivative, intermediate, and application thereof |
| CN113968798A (en) * | 2020-07-24 | 2022-01-25 | 沈阳中化农药化工研发有限公司 | Cyclohexyl ester compound, preparation method and application thereof |
| CN113968798B (en) * | 2020-07-24 | 2023-01-24 | 沈阳中化农药化工研发有限公司 | Cyclohexyl ester compound, preparation method and application thereof |
| US11970507B2 (en) | 2021-09-29 | 2024-04-30 | Oriental (Luzhou) Agrochemicals Co., Ltd. | Method for preparing 2-arylmalonic acid derivative and intermediate, and use thereof |
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