CN111635401A - Copper complex promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method - Google Patents
Copper complex promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method Download PDFInfo
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- CN111635401A CN111635401A CN202010562549.5A CN202010562549A CN111635401A CN 111635401 A CN111635401 A CN 111635401A CN 202010562549 A CN202010562549 A CN 202010562549A CN 111635401 A CN111635401 A CN 111635401A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- 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
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1825—Ligands comprising condensed ring systems, e.g. acridine, carbazole
- B01J31/183—Ligands comprising condensed ring systems, e.g. acridine, carbazole with more than one complexing nitrogen atom, e.g. phenanthroline
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
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Abstract
The invention belongs to the field of organic synthesis, fine chemicals and medical intermediates, and particularly relates to a method for synthesizing 7-fluoroimidazo [1,2-a ] pyridine from 2-amino-4-fluoropyridine and acetylene, which is promoted by a copper complex. The method is characterized in that a copper complex is used as a catalyst, and under the existence of peroxide, 2-amino-4-fluoropyridine and acetylene undergo an oxidative cycloaddition reaction to synthesize the 7-fluoroimidazole [1,2-a ] pyridine. The method is simple and convenient to operate, the reagent is cheap and easy to obtain, and the method has a good industrial application prospect.
Description
Technical Field
The invention relates to the technical field of organic synthesis and fine chemicals, in particular to a copper complex-promoted synthesis method of 7-fluoroimidazole [1,2-a ] pyridine.
Background
7-fluoroimidazo [1,2-a ] pyridine (CAS number 1260903-17-0), an important organic synthetic intermediate, is widely used in the synthesis of medicines, pesticides, and fine chemicals. For the synthesis method of 7-fluoroimidazole [1,2-a ] pyridine, although some documents report at present, several steps of reaction are often needed, the process is complex, and the cost is high. The invention provides a method for synthesizing 7-fluoroimidazole [1,2-a ] pyridine by using 2-amino-4-fluoropyridine and acetylene in one step. The method is characterized in that a copper complex is used as a catalyst, and under the existence of peroxide, 2-amino-4-fluoropyridine and acetylene generate (3 + 2) oxidation cycloaddition reaction, so that 7-fluoroimidazole [1,2-a ] pyridine is synthesized. The method is simple and convenient to operate, the reagent is cheap and easy to obtain, and the method has a good industrial application prospect.
Disclosure of Invention
The invention aims to provide a copper complex-promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method aiming at the defects in the prior art.
The technical scheme for solving the problems comprises the following steps: a copper complex promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method is a one-step synthesis method of 7-fluoroimidazo [1,2-a ] pyridine by taking 2-amino-4-fluoropyridine and acetylene as raw materials in the presence of a copper complex and peroxide. The copper complex is used as a catalyst to promote the [ 3+2 ] oxidative cycloaddition reaction of 2-amino-4-fluoropyridine and acetylene, and the specific reaction and the structural formula of the catalyst are shown in the following chart:
in the catalyst structure of the reaction, R1, R2, R3, R4, R5, R6 and R7 are hydrogen atoms or any of the same or different alkyl groups, aryl groups or heterocyclic groups.
In the structure of the catalyst for the reaction, [ Cu ] is copper ions with 0-1 anions, and the anions comprise chloride ions, bromide ions, iodide ions, trifluoromethanesulfonate ions, perchlorate ions, acetate ions and the like.
The amount of the catalyst substance is 1-5% of the amount of the 2-amino-4-fluoropyridine substance.
The peroxide is selected from sodium persulfate, Oxone, benzoyl peroxide and the like, and the amount ratio of the peroxide to the 2-amino-4-fluoropyridine is 1-1.2: 1.
the acetylene consumption of the reaction is measured by the pressure of acetylene gas in a reaction system, and the pressure of acetylene is kept at 1-5 standard atmospheric pressures in the reaction process.
The solvent for the reaction is selected from DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), DMSO (dimethyl sulfoxide), acetonitrile and the like.
The reaction temperature is 60-100 ℃.
The invention has the following beneficial effects:
the invention provides a copper complex-promoted 7-fluoroimidazo [1,2-a ] pyridine synthesis method, which is a method for synthesizing 7-fluoroimidazo [1,2-a ] pyridine by a one-step method in the presence of a copper complex and peroxide by taking 2-amino-4-fluoropyridine and acetylene as raw materials. The method is simple and convenient to operate, cheap and easily available in reagents, green, safe, efficient and environment-friendly, and is suitable for industrial production.
Drawings
FIG. 1: examples one to four nuclear magnetic resonance hydrogen spectra of the synthesized 7-fluoroimidazo [1,2-a ] pyridine.
FIG. 2: examples one to four high performance liquid chromatography of the synthesized 7-fluoroimidazo [1,2-a ] pyridine.
Detailed Description
The first embodiment is as follows:
112 g of 2-amino-4-fluoropyridine, 500mL of DMF as a solvent, 240 g of sodium persulfate and 6 g of catalyst were placed in succession in a 1000mL pressure reaction vessel. Then, acetylene gas was introduced while maintaining the pressure at 2 to 3 atmospheres, the reaction was carried out at 80 ℃ for 26 hours, and then, water and ethyl acetate were used for extraction three times to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporator to give 121 g of 7-fluoroimidazo [1,2-a ] pyridine in 89% yield.
Example two:
to a 1000mL pressure reaction vessel were added 112 g of 2-amino-4-fluoropyridine, 500mL of solvent DMSO, 620 g of Oxone, and 9 g of catalyst in this order. Then, acetylene gas was introduced while maintaining the pressure at 3 to 4 atmospheres, the reaction was carried out at 60 ℃ for 24 hours, and then, water and ethyl acetate were used for extraction three times to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporator to give 123 g of 7-fluoroimidazo [1,2-a ] pyridine in 90% yield.
Example three:
112 g of 2-amino-4-fluoropyridine, 500mL of acetonitrile solvent, 250 g of benzoyl peroxide and 12 g of catalyst were placed in a 1000mL pressure reaction vessel in this order. Then, acetylene gas was introduced while maintaining the pressure at 1 to 4 atmospheres, and after the reaction was carried out at a temperature of 100 ℃ for 28 hours, the reaction mixture was extracted with water and ethyl acetate three times to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporator to give 118 g of 7-fluoroimidazo [1,2-a ] pyridine in 87% yield.
Example four:
112 g of 2-amino-4-fluoropyridine, 500mL of solvent DMA, 240 g of sodium persulfate and 12 g of catalyst were placed in succession in a 1000mL pressure reaction vessel. Then, acetylene gas was introduced while maintaining the pressure at 2 to 3 atmospheres, the temperature was raised to 90 ℃ to react for 24 hours, and then water and ethyl acetate were extracted three times to remove the water layer, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by rotary evaporator to give 125 g of 7-fluoroimidazo [1,2-a ] pyridine in 92% yield.
The structure of 7-fluoroimidazo [1,2-a ] pyridine synthesized in the above examples was confirmed by hydrogen nuclear magnetic resonance spectroscopy (1H NMR) and High Performance Liquid Chromatography (HPLC) in fig. 1 and 2.
The above description is only a preferred embodiment of the present invention, and not intended to limit the present invention in other forms, and any person skilled in the art may apply the above modifications or changes to the equivalent embodiments with equivalent changes, without departing from the technical spirit of the present invention, and any simple modification, equivalent change and change made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the technical spirit of the present invention.
Claims (8)
1. The copper complex-promoted 7-fluoroimidazole [1,2-a ] pyridine synthesis method is characterized by comprising the following steps: a method for synthesizing 7-fluoroimidazole [1,2-a ] pyridine by using 2-amino-4-fluoropyridine and acetylene as raw materials in a one-step method in the presence of a copper complex and peroxide comprises the following specific reactions:
2. the copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: in the catalyst structure used in the reaction, R1, R2, R3, R4, R5, R6 and R7 are hydrogen atoms or any of the same or different alkyl groups, aryl groups or heterocyclic groups.
3. The copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: in the structure of the catalyst used in the reaction, [ Cu ] is copper ions with 0-1 anions, and the anions comprise chloride ions, bromide ions, iodide ions, trifluoromethanesulfonate ions, perchlorate ions and acetate ions.
4. The copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: the amount of the catalyst substance is 1-5% of the amount of the 2-amino-4-fluoropyridine substance.
5. The copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: the peroxide is selected from sodium persulfate, Oxone, benzoyl peroxide and the like, and the amount ratio of the peroxide to the 2-amino-4-fluoropyridine is 1-1.2: 1.
6. the copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: the acetylene consumption of the reaction is measured by the pressure of acetylene gas in a reaction system, and the pressure of acetylene is kept at 1-5 standard atmospheric pressures in the reaction process.
7. The copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: the solvent for the reaction is selected from DMF (N, N-dimethylformamide), DMA (N, N-dimethylacetamide), DMSO (dimethyl sulfoxide), acetonitrile and the like.
8. The copper complex-promoted synthesis of 7-fluoroimidazo [1,2-a ] pyridine as claimed in claim 1, characterized in that: the reaction temperature is 60-100 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112409354A (en) * | 2020-12-23 | 2021-02-26 | 苏利制药科技江阴有限公司 | Synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and intermediate thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838597A (en) * | 2012-09-10 | 2012-12-26 | 武汉大学 | Preparation method of heteroaromatic iminazole [1,2-Alpha]pyridine compounds |
| CN106065009A (en) * | 2014-06-28 | 2016-11-02 | 广东东阳光药业有限公司 | As the compound of hepatitis c inhibitor and the application in medicine thereof |
| WO2017005822A1 (en) * | 2015-07-06 | 2017-01-12 | Paris Sciences Et Lettres - Quartier Latin | Functionalizable molecular probe for x-ray fluorescence imaging and multimodal imaging |
| CN110467591A (en) * | 2019-08-23 | 2019-11-19 | 上海克琴科技有限公司 | Rare earth metal complex promote one pot process cosmetic active object Bose because |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838597A (en) * | 2012-09-10 | 2012-12-26 | 武汉大学 | Preparation method of heteroaromatic iminazole [1,2-Alpha]pyridine compounds |
| CN106065009A (en) * | 2014-06-28 | 2016-11-02 | 广东东阳光药业有限公司 | As the compound of hepatitis c inhibitor and the application in medicine thereof |
| WO2017005822A1 (en) * | 2015-07-06 | 2017-01-12 | Paris Sciences Et Lettres - Quartier Latin | Functionalizable molecular probe for x-ray fluorescence imaging and multimodal imaging |
| CN110467591A (en) * | 2019-08-23 | 2019-11-19 | 上海克琴科技有限公司 | Rare earth metal complex promote one pot process cosmetic active object Bose because |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112409354A (en) * | 2020-12-23 | 2021-02-26 | 苏利制药科技江阴有限公司 | Synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and intermediate thereof |
| CN112409354B (en) * | 2020-12-23 | 2021-10-08 | 苏利制药科技江阴有限公司 | Synthesis process of 7-fluoroimidazo [1,2-A ] pyridine and intermediate thereof |
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