CN104761503B - A kind of preparation method of azole amide compound - Google Patents
A kind of preparation method of azole amide compound Download PDFInfo
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- CN104761503B CN104761503B CN201510108433.3A CN201510108433A CN104761503B CN 104761503 B CN104761503 B CN 104761503B CN 201510108433 A CN201510108433 A CN 201510108433A CN 104761503 B CN104761503 B CN 104761503B
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- azole
- amide compound
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
A kind of preparation method of azole amide compound, the invention discloses one kind mantoquita for catalyst and molecular oxygen as oxidant under conditions of, pass through the reaction of carboxylic acid compound and azole compounds synthesis azole amide compound.This method uses cheap catalyst (mantoquita), molecular oxygen is as oxidant and reactant, azole amide compound is obtained by C sp3 decarboxylic reactions, molecular oxygen activation, benzyl subunit and azole amidation process, substrate spectrum is wide, and yield is high.The use copper catalysis of the method innovation of the present invention can directly carry out acylation reaction under conditions of no coupling agent, no activator by unactivated carboxylic acid compound and azole compounds, have potential application in organic chemical synthesis field.
Description
Technical field
The present invention relates to the field of chemical synthesis, and in particular to a kind of preparation method of azole amide compound.
Background technology
Azole, is to be widely used in organic compound important in bioactive natural products and pharmaceutically active molecule.Perhaps
More researchs are all unfolded around the formation of feature azole compounds.In them, since three-level amido link in the reaction can be with
After formation, the N- acylation reactions of azole compounds are just very noticeable.Although currently also exist in the research of generation amide Method
In progress, but practicality due to raw material and it is relatively friendly the characteristics of-water is unique accessory substance in reaction, amine and free carboxylic
The acylation reaction of acid or conventional and universal synthetic method.But free carboxy acid is frequently necessary to be activated, and theory is matched somebody with somebody
The activating reagent or coupling reagent of ratio all limit the formation of amidation process, in the case, corrosive accessory substance (HCl)
It cannot avoid.It is interesting that it is seldom example that the N- of azole compounds, which is acylated, and an aldehydes is only had been reported that recently
The N- acylation reactions of azole compounds occur under no metal catalytic with azole compounds.However, in this successfully reaction
Need excessive peroxide.According to recently in terms of environmental-friendly synthesis increasing need, it is necessary to which one suitable green
The azole compounds amidation process method of color practicality.
The content of the invention
It is an object of the invention to provide a kind of preparation method of azole amide compound.
The concrete technical scheme of the present invention is as follows：
A kind of preparation method of azole amide compound, is oxidant by catalyst, molecular oxygen of mantoquita, passes through carboxylic acids
Compound and azole compounds synthesis azole amide compound.By taking phenylacetic acid as an example, its reaction mechanism is as follows：
In a preferred embodiment of the invention, include the following steps：
(1) carboxylic acid compound, azole compounds, mantoquita are added to the solvent storage bottle containing organic solvent and pyridine
In, then pour oxygen and seal, stir 18-30h at 100-150 DEG C, wherein carboxylic acid compound and azole compounds
Molar ratio is 1:1-1:5；
(2) after the completion of reacting, organic solvent is evaporated by Rotary Evaporators, uses silicagel column purified product afterwards.
Preferably, the mantoquita is CuI, CuBr, CuBr2In one kind or its combination, dosage 5-10mol%.
Preferably, the carboxylic acid compound is phenylacetic acid, and the azole compounds are benzimidazole, phenylacetic acid and benzo
The molar ratio of imidazoles is 1:2；The reaction is to stir 24h at 120-140 DEG C.
Preferably, the carboxylic acid compound is phenylacetic acid class compound, phenylacetic acid class compound and azole compounds
Molar ratio is 1:2；The reaction is to stir 21-24h at 130-150 DEG C.
Preferably, the organic solvent includes paraxylene, ortho-xylene, meta-xylene, 1,3,5- trimethylbenzenes, first
Benzene, dimethyl sulfoxide (DMSO) (DMSO) and one kind in chlorobenzene (PhCl) or its combination.
Preferably, the eluant, eluent of step (2) the silica gel column purification is the mixed solution of petroleum ether and ethyl acetate, ratio
Scope is petroleum ether:Ethyl acetate=1:1-4.
The beneficial effects of the invention are as follows：
1st, the raw material of method of the invention is carboxylic acid compound and azole compounds, and catalyst is mantoquita, and oxidant is
Oxygen, is activated, benzyl subunit and azole amidation process obtain azole acid amides by C-sp3 decarboxylic reactions, molecular oxygen
Compound, innovative use copper catalysis is under conditions of no coupling agent, no activator by unactivated carboxylic acid and benzimidazole
Acylation reaction is directly carried out, reaction condition is gentle, and raw material is commonly easy to get, easy to operate, environmental protection and practicality；
2nd, method of the invention is suitable for carboxylic acid compound and various azole compounds amidatioons obtain azole amidatioon
Compound, substrate spectrum is wide, and compatibility is strong, and efficiency of pcr product is high, has extensive and important application.
Embodiment
Technical scheme is further detailed and described below by way of embodiment.
Embodiment 1
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of paraxylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
(2) after the completion of reacting, organic solvent is evaporated by Rotary Evaporators, uses silicagel column purified product, silicagel column afterwards
The eluant, eluent of purifying is petroleum ether and the mixed solution of ethyl acetate, and ratio is petroleum ether:Ethyl acetate=1:2, obtain benzo
Imidazoles 1- acyl group GC yield is 75%.
Embodiment 2
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuI (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of paraxylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C,；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 68%.
Embodiment 3
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of ortho-xylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 91%.
Embodiment 4
(1) by phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr2(10mol%) is added to containing pyridine
(3 equivalent), in the solvent storage bottle of ortho-xylene (1mL), then pours oxygen (airbag) and seals, stirred at 130 DEG C
24h；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 56%.
Embodiment 5
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of meta-xylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 39%.
Embodiment 6
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of 1,3,5- trimethylbenzene (1mL), then pour oxygen (airbag) and seal, stirred at 130 DEG C
Mix 24h；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 15%.
Embodiment 7
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of toluene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 43%.
Embodiment 8
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of DMSO (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 12%.
Embodiment 9
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of PhCl (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 77%.
Embodiment 10
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of ortho-xylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 140 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 75%.
Embodiment 11
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (3
Equivalent), in the solvent storage bottle of ortho-xylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 120 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 11%.
Embodiment 12
(1) phenylacetic acid (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%) are added to containing pyridine (2
Equivalent), in the solvent storage bottle of ortho-xylene (1mL), then pour oxygen (airbag) and seal, 24h is stirred at 130 DEG C；
For step (2) with embodiment 1, the GC yield of product benzimidazole 1- acyl groups is 48%.
Embodiment 13
(1) respectively by different phenylacetic acid class compounds (0.25mmol), azole compounds (0.5mmol), CuBr
(10mol%) is added to containing pyridine 0.75mmol, in the solvent storage bottle of ortho-xylene 1mL, then pours oxygen (airbag)
And seal stirring and make its reaction, reaction time 21-24h, reaction temperature is 130-150 DEG C.
Step (2) is as shown in table 1 with embodiment 1, the yield of each product and GC.
Table 1：
The preparation method of the present invention has good compatibility for various phenylacetic acid class compounds and azole compounds, point
From high income, have a wide range of applications.
Embodiment 14
(1) respectively by different carboxylic acid compounds (0.25mmol), benzimidazole (0.5mmol), CuBr (10mol%)
It is added to containing pyridine 0.75mmol, in the solvent storage bottle of ortho-xylene 1mL, then pours oxygen (airbag) and seal stirring
Make its reaction, reaction time 20h, reaction temperature is 130 DEG C.
For step (2) with embodiment 1, the yield of its product and GC are as shown in table 2.
Table 2：
In above-described embodiment, the reaction of copper catalysis oxidation has well on various carboxylic acid compounds and azole compounds
Effect.Acetophenone derivs substitution of functional groups on aromatic ring can be very good compatibility in the reaction.Among them,
The reaction of ring substitute group has obtained corresponding product, and this further demonstrates the feasibility of this reaction；Alkyl and alkoxy
Substitution of the group on aromatic ring all obtains good reaction.Polyphenylene group, if 1- naphthyls and 2- naphthyl acetic acids are in standard bar
It is all compatible well and obtain the corresponding good yield of product under part.Benzenpropanoic acid and its derivative and 2-Hydroxyphenyl Acetic Acid and its
Derivative also can be very good to react, and generate the corresponding product of good yield, and benzoyl formic acid can also obtain height in addition
The corresponding product of yield.
The method reaction condition of the present invention is gentle, raw material is easy to get, the good compatibility to various reactants, and practicality is extensive,
Yield is high, can be widely applied in various functionsization reaction.
The foregoing is only a preferred embodiment of the present invention, therefore cannot limit the scope that the present invention is implemented according to this, i.e.,
The equivalent changes and modifications made according to the scope of the claims of the present invention and description, all should still belong to the scope that the present invention covers.
Claims (5)
- A kind of 1. preparation method of azole amide compound, it is characterised in that：It is oxidant by catalyst, molecular oxygen of mantoquita, Azole amide compound is synthesized by carboxylic acid compound and azole compounds；The preparation method specifically comprises the following steps：(1) carboxylic acid compound, azole compounds, mantoquita are added in the solvent storage bottle containing organic solvent and pyridine, It is then charged with oxygen and seals, mole of 18-30h, wherein carboxylic acid compound and azole compounds is stirred at 100-150 DEG C Than for 1:1-1:5；(2) after the completion of reacting, organic solvent is evaporated by Rotary Evaporators, uses silicagel column purified product afterwards；Obtained azole amide compound structural formula is one of following：
- 2. the preparation method of azole amide compound as claimed in claim 1, it is characterised in that：The mantoquita be CuI, CuBr、CuBr2In one kind or its combination, dosage 5-10mol%.
- 3. the preparation method of azole amide compound as claimed in claim 1, it is characterised in that：The carboxylic acid compound is Phenylacetic acid, the azole compounds are benzimidazoles, and the molar ratio of phenylacetic acid and benzimidazole is 1:2；It is described reaction be 24h is stirred at 120-140 DEG C.
- 4. the preparation method of azole amide compound as claimed in claim 1, it is characterised in that：The organic solvent include pair Dimethylbenzene, ortho-xylene, meta-xylene, 1,3,5- trimethylbenzenes, toluene, dimethyl sulfoxide (DMSO) and one kind or its group in chlorobenzene Close.
- 5. the preparation method of azole amide compound as claimed in claim 1, it is characterised in that：Step (2) silicagel column The eluant, eluent of purifying is petroleum ether and the mixed solution of ethyl acetate, and proportion is petroleum ether:Ethyl acetate=1:1-4.
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