CN109503501A - DBU class ionic liquid is promoting without the application in copper Click reaction - Google Patents
DBU class ionic liquid is promoting without the application in copper Click reaction Download PDFInfo
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- CN109503501A CN109503501A CN201811428660.4A CN201811428660A CN109503501A CN 109503501 A CN109503501 A CN 109503501A CN 201811428660 A CN201811428660 A CN 201811428660A CN 109503501 A CN109503501 A CN 109503501A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0278—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre
- B01J31/0281—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member
- B01J31/0282—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature containing nitrogen as cationic centre the nitrogen being a ring member of an aliphatic ring, e.g. morpholinium
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0298—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature the ionic liquids being characterised by the counter-anions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/02—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length in solution
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Analytical Chemistry (AREA)
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Abstract
The invention discloses a kind of DBU class ionic liquids to promote to belong to no copper Click catalytic reaction system technical field without the application in copper Click reaction.Technical solution of the present invention main points are as follows:
Description
Technical field
The invention belongs to no copper Click catalytic reaction system technical fields, and in particular to a kind of DBU class ionic liquid is promoting
Application into no copper Click reaction.
Background technique
With the development of proteomics and field of biomedicine, the rear modification of polypeptide is aroused widespread concern.
By the rear modification to polypeptide, the modification to some active peptides is may be implemented in people.And Click reaction have be simple and efficient with
And the features such as highly selective, it is suitable for conjugated biological molecules and artificial ligand, and what is generated contains 1,2,3- triazole structures
Molecule is found to have the antiviral of wide spectrum, antibacterial, antimycotic and anticancer bioactive, such as bis- virtue of 4- alkoxy carbonyl -1,5-
Base -1,2,3- 3-triazole compounds are confirmed to be effective CB1 Cannabined receptor inhibitor.
However the modification of polypeptide is generally required and is carried out under condition (such as physiological conditions) as mild as a dove, it is more convenient for retaining
The structural intergrity of the biomolecule such as peptide.Classical Huisgen 1,3- Dipolar Cycloaddition is original using end alkynes and nitrine
Material generates Isosorbide-5-Nitrae-substitution and 1,1,2, the 3- triazole mixtures that 5- replaces, and needs to be heated at high temperature during the reaction.
The end alkynes of the copper catalysis of Sharpless and Medal group discovery and the Dipolar Cycloaddition (CuAAC reaction) of nitrine can
1,2,3- triazoles of Isosorbide-5-Nitrae substitution are efficiently prepared in a mild condition, but the copper catalyst that CuAAC reaction uses does not have
Ideal bio-compatibility.Therefore, the Click reaction of no metal catalytic causes the extensive concern of people.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of simple process and the mild DBU class ionic liquids of reaction condition
Promoting without the application in copper Click reaction.
The present invention adopts the following technical scheme that DBU class ionic liquid is promoting without copper Click to solve above-mentioned technical problem
Application in reaction, it is characterised in that: using DBU class ionic liquid simultaneously as solvent and catalyst, the DBU class in reaction process
The cation of ionic liquid are as follows:The anion of DBU class ionic liquid are as follows:
Further preferably, the DBU class ionic liquid is promoting without the application in copper Click reaction, it is characterised in that tool
Body process are as follows: using O-methoxy benzyl azide and N- acetoacetanilide as reaction raw materials, using DBU class ionic liquid simultaneously as
Target product, the specific synthetic route of synthesis process is made in 50 DEG C of reaction 2h in solvent and catalyst are as follows:
Further preferably, the O-methoxy benzyl azide, N- acetoacetanilide and feeding intake for DBU class ionic liquid are rubbed
You are than being 1:1:1.
Further preferably, the DBU class ionic liquid is preferably DBU acetate.
Further preferably, the DBU class ionic liquid is promoting without the application in copper Click reaction, it is characterised in that tool
Body step are as follows: O-methoxy benzyl azide, N- acetoacetanilide and DBU class ionic liquid are sequentially added in the reaction vessel,
2h is stirred to react in 50 DEG C, TLC is detected in reaction process, uses the mixed extractant solvent of ethyl acetate and distilled water after reaction
It is spin-dried for obtaining crude product, the crude product is through the isolated target product of silica gel column chromatography.
Further preferably, the volume ratio of the in the mixed solvent ethyl acetate and distilled water of the ethyl acetate and distilled water is
1:1。
Further preferably, the DBU class ionic liquid is promoting to carry out the application in peptide modified without copper Click reaction,
It is characterized in that specific synthetic route are as follows:
Further preferably, the DBU class ionic liquid is promoting to carry out the application in peptide modified without copper Click reaction,
It is characterized in that specific steps are as follows: peptide chain 1y, acetoacetyl methylamine and the ionic liquid of the nitrine containing end group are added in the reaction vessel
Body DBU acetate is stirred to react 8h in 37 DEG C, and analysis HPLC monitoring, after reaction, system is dissolved in 10wt% acetonitrile solution
In, preparation HPLC separation collects product peak, Click is obtained after freeze-drying and reacts peptide modified product.
Further preferably, the throwing of the peptide chain 1y, acetoacetyl methylamine and ionic liquid DBU acetate of the nitrine containing end group
Material molar ratio is 14:17:28.
Compared with the prior art, the present invention has the following advantages:
It 1, is no copper Click reaction model with O-methoxy benzyl azide and the N- acetoacetanilide containing amido bond,
Filter out preferable ionic liquid, and be applied in peptide modified；
2, the reaction system does not add copper and other metallic catalysts using ionic liquid as solvent and catalyst, and has
Avoid to effect the use of organic solvent；
3, reaction condition is mild, remains the integrality of polypeptide structure.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
Meta-methoxy benzyl azide 0.20mmol, ethyl acetoacetate 0.20mmol is taken to be placed in dry reaction flask, so
DBU acetate ion liquid 0.20mmol is added afterwards, is stirred to react 2h in 50 DEG C, reaction process is detected with TLC, after reaction
The mixed extractant solvent of the ethyl acetate and distilled water that are 1:1 with volume ratio is spin-dried for obtaining crude product, and the crude product is through silicagel column
Chromatographic isolation obtains target product, and separation yield is 92%.
Embodiment 2
Meta-methoxy benzyl azide 0.20mmol, ethyl acetoacetate 0.20mmol is taken to be placed in dry reaction flask, so
DBU amine formate ionic liquid 0.20mmol is added afterwards, is stirred to react 2h in 50 DEG C, reaction process is detected with TLC, after reaction
The mixed extractant solvent of the ethyl acetate and distilled water that are 1:1 with volume ratio is spin-dried for obtaining crude product, and the crude product is through silicagel column
Chromatographic isolation obtains target product, and separation yield is 85%.
Embodiment 3
Meta-methoxy benzyl azide 0.20mmol, ethyl acetoacetate 0.20mmol is taken to be placed in dry reaction flask, so
DBU propionic acid ionic liquid 0.20mmol is added afterwards, is stirred to react 2h in 50 DEG C, reaction process is detected with TLC, after reaction
The mixed extractant solvent of the ethyl acetate and distilled water that are 1:1 with volume ratio is spin-dried for obtaining crude product, and the crude product is through silicagel column
Chromatographic isolation obtains target product, and separation yield is 89%.
Embodiment 4
Meta-methoxy benzyl azide 0.20mmol, ethyl acetoacetate 0.20mmol is taken to be placed in dry reaction flask, so
DBU butyric acid ionic liquid 0.20mmol is added afterwards, is stirred to react 2h in 50 DEG C, reaction process is detected with TLC, after reaction
The mixed extractant solvent of the ethyl acetate and distilled water that are 1:1 with volume ratio is spin-dried for obtaining crude product, and the crude product is through silicagel column
Chromatographic isolation obtains target product, and separation yield is 70%.
Embodiment 5
Meta-methoxy benzyl azide 0.20mmol, ethyl acetoacetate 0.20mmol is taken to be placed in dry reaction flask, so
DBU glycollate ionic liquid 0.20mmol is added afterwards, is stirred to react 2h in 50 DEG C, reaction process is detected with TLC, and reaction terminates
The mixed extractant solvent of the ethyl acetate and distilled water that are afterwards 1:1 with volume ratio is spin-dried for obtaining crude product, and the crude product is through silica gel
Pillar layer separation obtains target product, and separation yield is 89%.
Embodiment 6
Meta-methoxy benzyl azide 0.20mmol, ethyl acetoacetate 0.20mmol is taken to be placed in dry reaction flask, so
DBU isovalerate ionic liquid 0.20mmol is added afterwards, is stirred to react 2h in 50 DEG C, reaction process is detected with TLC, and reaction terminates
The mixed extractant solvent of the ethyl acetate and distilled water that are afterwards 1:1 with volume ratio is spin-dried for obtaining crude product, and the crude product is through silica gel
Pillar layer separation obtains target product, and separation yield is 70%.
Embodiment 7
Peptide chain 1y 0.014mmol containing end group nitrine, acetoacetyl methylamine 0.017mmol is taken to be placed in dry reaction
In bottle, ionic liquid DBU acetate 0.028mmol is then added, is stirred to react 8h in 37 DEG C, after reaction, system is dissolved in
In 10wt% acetonitrile solution, preparation HPLC separation.Using contain 0.1wt%TFA aqueous solution and 0.1wt%TFA acetonitrile solution
Linear gradient elution pillar obtains Click reaction modified outcome, yield 80% after freeze-drying.Use Mass Spectrometer Method molecule
Amount find [M+H] +=805.80.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (9)
1.DBU class ionic liquid promote without copper Click reaction in application, it is characterised in that: in reaction process with DBU class from
Sub- liquid is used as solvent and catalyst simultaneously, the cation of the DBU class ionic liquid are as follows:DBU class ionic liquid
Anion are as follows:
2. DBU class ionic liquid according to claim 1 is promoting without the application in copper Click reaction, it is characterised in that
Detailed process are as follows: using O-methoxy benzyl azide and N- acetoacetanilide as reaction raw materials, made simultaneously with DBU class ionic liquid
For solvent and catalyst, target product, the specific synthetic route of synthesis process is made in 50 DEG C of reaction 2h are as follows:
3. DBU class ionic liquid according to claim 2 is promoting without the application in copper Click reaction, it is characterised in that:
The molar ratio of the O-methoxy benzyl azide, N- acetoacetanilide and DBU class ionic liquid is 1:1:1.
4. DBU class ionic liquid according to claim 1 or 2 is promoting without the application in copper Click reaction, feature exists
In the DBU class ionic liquid be preferably DBU acetate.
5. DBU class ionic liquid according to claim 1 or 2 is promoting without the application in copper Click reaction, feature exists
In specific steps are as follows: sequentially add O-methoxy benzyl azide, N- acetoacetanilide and DBU class ionic liquid in the reaction vessel
Body is stirred to react 2h in 50 DEG C, and TLC is detected in reaction process, uses the mixed solvent of ethyl acetate and distilled water after reaction
Extraction is spin-dried for obtaining crude product, and the crude product is through the isolated target product of silica gel column chromatography.
6. DBU class ionic liquid according to claim 5 is promoting without the application in copper Click reaction, it is characterised in that:
The volume ratio of the in the mixed solvent ethyl acetate and distilled water of the ethyl acetate and distilled water is 1:1.
7. DBU class ionic liquid according to claim 1 is promoting without the application in copper Click reaction, it is characterised in that:
The DBU class ionic liquid is promoting to carry out the application in peptide modified, specific synthetic route without copper Click reaction are as follows:
8. DBU class ionic liquid according to claim 7 is promoting without the application in copper Click reaction, it is characterised in that
Specific steps are as follows: the peptide chain 1y, acetoacetyl methylamine and ionic liquid DBU acetic acid of the nitrine containing end group are added in the reaction vessel
Salt is stirred to react 8h in 37 DEG C, and analysis HPLC monitoring, after reaction, system is dissolved in 10wt% acetonitrile solution, preparation
HPLC separation, collects product peak, and Click is obtained after freeze-drying and reacts peptide modified product.
9. DBU class ionic liquid according to claim 7 or 8 is promoting without the application in copper Click reaction, feature exists
In: peptide chain 1y, acetoacetyl methylamine and the molar ratio of ionic liquid DBU acetate of the nitrine containing end group are 14:17:
28。
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| CN201811428660.4A CN109503501B (en) | 2018-11-27 | 2018-11-27 | Application of DBU ionic liquid in promotion of copper-free Click reaction |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811428660.4A CN109503501B (en) | 2018-11-27 | 2018-11-27 | Application of DBU ionic liquid in promotion of copper-free Click reaction |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439967A (en) * | 2015-12-12 | 2016-03-30 | 青岛大学 | Synthetic method of 1,4,5-trisubstituted-1,2,3-triazole compound |
| CN105949240A (en) * | 2016-05-13 | 2016-09-21 | 河南师范大学 | Method for synthesizing 4-phosphonic acid-1,5-substituted-1,2,3 triazole compounds through catalysis of ionic liquid |
| CN107245072A (en) * | 2016-11-18 | 2017-10-13 | 河南师范大学 | A kind of preparation method of the triazole compound of Tarceva 1,2,3 |
-
2018
- 2018-11-27 CN CN201811428660.4A patent/CN109503501B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439967A (en) * | 2015-12-12 | 2016-03-30 | 青岛大学 | Synthetic method of 1,4,5-trisubstituted-1,2,3-triazole compound |
| CN105949240A (en) * | 2016-05-13 | 2016-09-21 | 河南师范大学 | Method for synthesizing 4-phosphonic acid-1,5-substituted-1,2,3 triazole compounds through catalysis of ionic liquid |
| CN107245072A (en) * | 2016-11-18 | 2017-10-13 | 河南师范大学 | A kind of preparation method of the triazole compound of Tarceva 1,2,3 |
Non-Patent Citations (6)
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