A method for synthesizing imidazo[1,2-a]pyridine compounds

Abstract

The application discloses a synthesis method of imidazo[1,2-a]pyridine compounds, which is synthesized by cyclization of a compound of formula III under electrochemical conditions and in the presence of a catalyst to obtain an imidazo[1,2-a]pyridine compound of formula IV. The electrochemical conditions include adding an electrolyte in a solvent, applying a current of 5-20 mA, a reaction temperature of 45-60 DEG C, and a reaction time of 2-8 hours; the solvent is selected from ethanol or isopropanol; and the electrolyte is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate and tetraethylammonium hexafluorophosphate.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing imidazo[1,2-a]pyridine compounds. Background Technology

[0002] Imidazolo[1,2-a]pyridine is an extremely important class of nitrogen-containing heterocyclic aromatic compounds. Currently, derivatives based on the imidazo[1,2-a]pyridine structure are widely used in medicinal chemistry and materials science. Imidazolo[1,2-a]pyridine derivatives possess good pharmaceutical activities, such as antiviral, antitumor, anti-inflammatory, sedative-hypnotic, and anti-ulcer effects. Common drugs such as salipyridamole, zolpidem, and zolpidem all contain the imidazo[1,2-a]pyridine structure. Currently, the main method for synthesizing imidazo[1,2-a]pyridine is the cyclization condensation reaction of 2-aminopyridine with α-haloacetophenone. In addition, methods such as copper-catalyzed cyclization addition of nitrostyrene with 2-aminopyridine and cyclization coupling reactions of activated pyridine with other compounds have also been reported. However, existing methods for synthesizing imidazo[1,2-a]pyridine have some drawbacks, such as harsh reaction conditions and the use of stoichiometric oxidants. These drawbacks limit the industrial synthesis of imidazo[1,2-a]pyridine derivatives. Furthermore, the prior patent CN118186409A mentions an electrochemical method for synthesizing bisimizo[1,2-a]pyridine compounds, but this compound cannot further modify the imidazolium position, limiting its further application. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for synthesizing imidazo[1,2-a]pyridine compounds with mild reaction conditions and no need for equivalent oxidant, which is environmentally friendly.

[0004] To solve the above-mentioned technical problems, the present invention provides a method for synthesizing imidazo[1,2-a]pyridine compounds, which involves cyclizing a compound of formula III under electrochemical conditions and in the presence of a catalyst to obtain an imidazo[1,2-a]pyridine compound of formula IV:

[0005]

[0006] In Formulas III and IV, R is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C5-C15 heteroaryl, or protecting group, wherein each substituent is independently selected from halogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0007] Ar is selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted heterocyclic groups.

[0008] Preferably, the electrochemical conditions include adding an electrolyte to the solvent and applying a current of 5-20 mA, a reaction temperature of 45-60°C, and a reaction time of 2-8 hours; the solvent is selected from ethanol or isopropanol; the electrolyte is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate, and tetraethylammonium hexafluorophosphate.

[0009] In this invention, the imidazo[1,2-a]pyridine compounds can be synthesized in conventional solvents such as ethanol, with a reaction temperature not exceeding 120°C, preferably not exceeding 100°C. The overall reaction conditions are mild, requiring no oxidants or other materials, making it highly practical and easy for industrial-scale production. Furthermore, the imidazo[1,2-a]pyridine compounds synthesized in this invention have a vacancy at position 2, facilitating subsequent reactions and further modification. The acyl group can also be further modified, greatly expanding their modifiability.

[0010] In one specific embodiment, the molar ratio of the compound of formula III to the catalyst is 1:0.2-0.8; the molar ratio of the compound of formula III to the electrolyte is 1:0.05-0.4.

[0011] In one specific embodiment, the catalyst is selected from one or more of sodium iodide, potassium iodide, amine iodide, and hydroiodic acid.

[0012] In one specific implementation, the reaction process is monitored using a thin-layer chromatography plate.

[0013] In one specific embodiment, after the reaction is complete, the reaction system is concentrated and separated by column chromatography to obtain compound of formula IV. Understandably, the post-processing of this invention is also relatively simple.

[0014] In one specific embodiment, compound III is obtained by reacting compound I and compound II:

[0015]

[0016] In Formulas 1 and 3, R is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C5-C15 heteroaryl or protecting group, wherein each substituent is independently selected from halogen, C1-C6 alkyl or C1-C6 alkoxy;

[0017] Ar is selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted heterocyclic groups;

[0018] In Formula II, X is a halogen.

[0019] In one specific embodiment, the reaction conditions for the compound of formula III include:

[0020] Ethanol and / or isopropanol are used as solvents, and triethylamine is added thereto;

[0021] The reaction temperature is 80-120℃;

[0022] The reaction time is 1-3 hours.

[0023] In one specific embodiment, the molar ratio of compound I to compound II is 1:0.8-2.0; the molar ratio of compound I to triethylamine is 1:2.0-4. Detailed Implementation

[0024] The technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0025] Example 1: Synthesis of Compound 1

[0026]

[0027] S1. 10.8 mmol of 2-aminopyridine, 9 mmol of 3-chloro-1-(p-tolyl)prop-1-one, and 12.5 mmol of triethylamine were added to 10 mL of ethanol. The reaction mixture was stirred in a microwave at 100 °C for 0.5 hours, and the reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction mixture was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 1.1 g of intermediate, a yellow solid, in 51% yield.

[0028] S2. 50 mg of the intermediate, 15 mg of sodium iodide, and 35 mg of tetrabutylammonium tetrafluoroborate were added sequentially to a single-cell reactor, followed by 6 mL of ethanol. The reaction was carried out at 50 °C with a carbon rod as the anode and a platinum sheet as the cathode, and a constant current of 10 mA was applied for 4 hours. The reaction progress was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 40 mg of compound 1 as a yellow solid, with a yield of 81%.

[0029] Characterization data: 1H NMR(400MHz,CHLOROFORM-d)δppm 2.48(s,3H)7.17(t,J=6.88Hz,1H)7.35(d,J=8.00Hz,2H)7.57(dd,J=8.50,7.2 5Hz,1H)7.79-7.86(m,3H)8.21-8.26(m,1H)8.23(s,1H)9.75(d,J=6.88Hz,1H)

[0030] 13 C NMR (101MHz, CHLOROFORM-d) δppm 21.65, 115.05, 117.75, 123.65, 128.91, 129.04, 129.32, 136.60, 142.80, 145.36, 149.01, 184.71.

[0031] In this embodiment, when acetonitrile is used as the solvent in S2, although products are produced, the yield is extremely low and there are too many byproducts, making it unsuitable for industrial production. Therefore, ethanol and / or isopropanol are preferred as solvents.

[0032] Example 2-14

[0033] Following similar steps to Example 1, Examples 2-14 were obtained, wherein the raw materials, intermediates and products are detailed in Table 1.

[0034]

[0035]

[0036]

[0037]

[0038] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing imidazo[1,2-a]pyridine compounds, characterized in that, The imidazo[1,2-a]pyridine compounds of formula IV were synthesized by cyclization of the compound of formula III under electrochemical conditions and in the presence of a catalyst. ， In Formulas III and IV, R is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C6-C20 aryl, and substituted or unsubstituted C5-C15 heteroaryl. Each substituent is independently selected from halogens, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Ar is selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted heterocyclic groups; The catalyst is selected from one or more of sodium iodide, potassium iodide, amine iodide, and hydroiodic acid; The electrochemical conditions include adding an electrolyte to the solvent and applying a current of 5-20 mA, with a reaction temperature of 45-60 °C. The carbon rod is used as the anode, and the platinum sheet is used as the cathode. The solvent is selected from ethanol or isopropanol, and the electrolyte is selected from one or more of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate, and tetraethylammonium hexafluorophosphate.

2. The synthesis method according to claim 1, characterized in that, The reaction time is 2-8 hours.

3. The synthesis method as described in claim 2, characterized in that, The molar ratio of compound III to catalyst is 1:0.2-0.8; the molar ratio of compound III to electrolyte is 1:0.05-0.

4.

4. The synthesis method according to claim 1, characterized in that, The reaction process was monitored using thin-layer chromatography plates.

5. The synthesis method according to claim 1, characterized in that, After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain compound IV.

6. The synthesis method according to claim 1, characterized in that, Compound III is obtained by reacting compound I and compound II: ， In Formulas 1 and 3, R is selected from H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C6-C20 aryl, and substituted or unsubstituted C5-C15 heteroaryl. Each substituent is independently selected from halogens, C1-C6 alkyl groups, or C1-C6 alkoxy groups; Ar is selected from substituted or unsubstituted phenyl groups and substituted or unsubstituted heterocyclic groups; In Formula II, X is a halogen.

7. The synthesis method according to claim 6, characterized in that, The reaction conditions include: Ethanol and / or isopropanol are used as solvents, and triethylamine is added thereto; The reaction temperature is 80-120℃; The reaction time is 1-3 hours.

8. The synthesis method according to claim 7, characterized in that, The molar ratio of compound I to compound II is 1:0.8-2.0; the molar ratio of compound I to triethylamine is 1:2.0-4.

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