Synthetic method of 6-phenyl-imidazopyridine-2-amine

Abstract

The invention discloses a synthesis method of 6-phenyl-imidazopyridine-2-amine, and belongs to the technical field of synthesis of medical intermediates. The synthesis method provided by the invention comprises the following steps: under the catalytic action of benzenesulfonic acid, carrying out chlorination reaction on 6-phenyl-imidazopyridine and dichlorodimethylhydantoin, so as to obtain 2-chloro-6-phenyl-imidazopyridine; the method comprises the following steps: under the action of alkali and a bipyridine ligand, carrying out amination reaction on 2-chloro-6-phenyl-imidazopyridine and nickel hexammine dichloride, so as to obtain 6-phenyl-imidazopyridine-2-amine. The synthesis method provided by the invention is simple to operate, mild in condition and relatively low in cost of reaction raw materials, the total yield of two steps is 50% or above, the highest yield can reach 63%, and the synthesis method has a good application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for synthesizing 6-phenyl-imidazo[1,2-a]pyridin-2-amine. Background Art

[0002] The information disclosed in the background art of the present invention is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an indication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] With the increasing severity of the problem of bacterial resistance worldwide, the efficacy of traditional antibiotics has gradually weakened, and there is an urgent need to develop new antibacterial agents to address these challenges. Bacterial resistance is mainly manifested in the fact that bacteria gradually develop resistance to existing antibiotics through mutation and horizontal gene transfer, especially significant resistance to commonly used β-lactams, fluoroquinolones, and macrolide antibiotics, etc. According to the report of the World Health Organization (WHO), drug resistance has become a major threat to global public health. Among many bacterial targets, DNA gyrase and topoisomerase IV are important enzymes that play crucial roles in the processes of bacterial DNA replication and transcription. Fluoroquinolone antibiotics exert antibacterial effects by inhibiting the functions of these two enzymes and interfering with the bacterial DNA synthesis process. However, with the widespread use of fluoroquinolone drugs, bacteria have developed resistance to these antibiotics, resulting in a significant decline in their clinical efficacy, and there is an urgent need to develop new inhibition mechanisms and treatment strategies. Against this background, arylimidazole compounds have attracted extensive attention from scientists (J. Med.Chem., 2008, 51, 5243). Arylimidazole-2-amine derivatives not only have unique structures but also possess various biological activities, especially antibacterial activity being the most prominent. By inhibiting DNA gyrase and topoisomerase IV, arylimidazole-2-amine derivatives can effectively inhibit the proliferation of bacteria and exhibit excellent activities against a variety of drug-resistant strains. Therefore, arylimidazole-2-amine derivatives are considered potential substitutes for fluoroquinolone antibiotics, especially having important clinical application prospects in dealing with drug-resistant bacterial infections.

[0004] Although the antibacterial activity of arylimidazole compounds has been demonstrated, there are still certain challenges in their synthesis methods. Existing synthetic routes usually involve multiple steps, with complex reaction conditions and low yields, and sometimes highly toxic chemical reagents are also required. Therefore, how to develop an efficient, simple, and economical synthesis method for arylimidazole-2-amine derivatives has become an important topic in the fields of synthetic chemistry and medicinal chemistry. Summary of the Invention

[0005] In view of this, the present invention provides a method for synthesizing 6-phenyl-imidazo[1,2-a]pyridin-2-amine compounds, which solves the problems of low raw material safety, high cost and low conversion rate in the synthesis of 6-phenyl-imidazo[1,2-a]pyridin-2-amine compounds in the prior art.

[0006] The present invention provides a method for synthesizing 6-phenyl-imidazo[1,2-a]pyridin-2-amine compounds, comprising the following steps: Under the catalytic action of benzenesulfonic acid, 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin undergo a chlorination reaction to obtain 2-chloro-6-phenyl-imidazo[1,2-a]pyridine; under the action of a base and a bipyridine ligand, 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel dichloride undergo an amination reaction to obtain 6-phenyl-imidazo[1,2-a]pyridin-2-amine.

[0007] Preferably, in the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the catalyst used is inexpensive benzenesulfonic acid.

[0008] Preferably, in the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the solvent used is one of hexafluoroisopropanol and trifluoroethanol.

[0009] Preferably, in the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the reaction temperature is 40-110 °C and the reaction time is 12-30 hours.

[0010] Preferably, in the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the molar ratio of 6-phenyl-imidazo[1,2-a]pyridine, dichlorodimethylhydantoin and benzenesulfonic acid is 1:(0.5-0.8):(0.03-0.1).

[0011] Preferably, in the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel dichloride, the ligand used is bipyridine.

[0012] Preferably, in the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel dichloride, the base used is one of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0013] Preferably, in the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel dichloride, the solvent used is one of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and acetonitrile.

[0014] Preferably, in the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel dichloride, the reaction temperature is 60-130 °C and the reaction time is 15-30 hours.

[0015] Preferably, in the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) chloride, the molar ratio of 2-chloro-6-phenylimidazo[1,2-a]pyridine, hexaamminenickel(II) chloride, 2,2'-bipyridine and base is 1:(0.35 - 0.5):(0.05 - 0.1):(1.0 - 1.5).

[0016] Compared with the prior art, the present invention has achieved the following beneficial effects: The present invention uses 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin as raw materials, and undergoes a chlorination reaction under the catalysis of benzenesulfonic acid to obtain 2-chloro-6-phenylimidazo[1,2-a]pyridine; 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) chloride undergo an amination reaction under the action of a base and 2,2'-bipyridine to obtain 6-phenyl-imidazo[1,2-a]pyridin-2-amine. The synthesis method provided by the present invention has simple operation, mild conditions and low cost of reaction raw materials. The total yield of the two steps is above 50% and can reach up to 63% at most, having good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The accompanying drawings forming a part of this specification are used to provide a further understanding of the present invention. The schematic embodiments and descriptions thereof of the present invention are used to explain the present invention and do not constitute an improper limitation to the present invention. Obviously, for those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0018] Figure 1 is the 1H NMR spectrum of the product 6-phenyl-imidazo[1,2-a]pyridin-2-amine in Example 1 of the present invention.

[0019] Figure 2 is the 13C NMR spectrum of the product 6-phenyl-imidazo[1,2-a]pyridin-2-amine in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0020] It should be noted that the following detailed description is exemplary and is intended to provide further illustration of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs. In order to enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions of the present invention will be described in detail below in combination with specific examples and comparative examples.

[0021] Example 1

[0022] 6-Phenyl-imidazole (19.52 g, 0.10 mol), dichlorodimethylhydantoin (11.82 g, 0.06 mol) and benzenesulfonic acid (0.79 g, 5 mmol) were dissolved in hexafluoroisopropanol (80 mL) under air. The mixture was stirred at 70 °C for 24 hours. After the reaction was complete, it was cooled to room temperature, and most of the organic solvent was removed by distillation under reduced pressure. Ethyl acetate (80 mL) was added, and the mixture was extracted and separated with saturated aqueous Na2S2O3 solution (20 mL). The solvent was removed by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain 18.60 g of 2-chloro-6-phenylimidazo[1,2-a]pyridine, with a yield of 81%.

[0023] Under a nitrogen atmosphere, 2-chloro-6-phenylimidazo[1,2-a]pyridine (2.30 g, 10 mmol), hexamminenickel(II) chloride (0.81 g, 3.5 mmol), and bipyridine (78.1 mg, 0.5 mmol) were added to a reaction flask. While stirring, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.98 g, 13 mmol) and DMF (15 mL) were added. The mixture was heated to 90 °C and stirred for 24 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (3 × 50 mL). The solvent was removed from the organic phase by distillation under reduced pressure, and the crude product was separated by column chromatography to obtain 1.64 g of 6-phenylimidazo[1,2-a]pyridin-2-amine, with a yield of 78%.

[0024] 1H NMR data of 6-phenylimidazo[1,2-a]pyridin-2-amine: NMR (500 MHz, DMSO) δ 8.21 (d, J = 1.8 Hz, 1H), 7.71 – 7.59 (m, 3H), 7.45 (t, J = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 6.75 (s, 2H). 13C NMR (126 MHz, DMSO) δ 157.9, 154.3, 139.6, 138.4, 130.8, 129.3, 128.2, 127.1, 127.0, 115.3.

[0025] Example 2

[0026]

[0027] Dissolve 6-phenyl-imidazole (19.52 g, 0.10 mol), dichlorodimethylhydantoin (15.76 g, 0.08 mol) and benzenesulfonic acid (0.79 g, 5 mmol) in hexafluoroisopropanol (80 mL) under air. Stir the mixture at 70 °C for 24 hours. After the reaction is complete, cool it to room temperature and distill off most of the organic solvents under reduced pressure. Extract and separate with ethyl acetate (80 mL) and saturated aqueous Na2S2O3 solution (20 mL). Distill off the solvent under reduced pressure. The crude product is separated by column chromatography to obtain 2-chloro-6-phenyl-imidazo[1,2-a]pyridine 18.14 g, with a yield of 79%.

[0028] Under a nitrogen atmosphere, add 2-chloro-6-phenyl-imidazo[1,2-a]pyridine (2.30 g, 10 mmol), nickel(II) hexammine dichloride (0.93 g, 4.0 mmol), 2,2'-bipyridine (78.1 mg, 0.5 mmol) to the reaction flask. While stirring, add 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.98 g, 13 mmol) and DMF (15 mL). Heat to 90 °C and stir for 24 hours. After the reaction is completed, cool it to room temperature, dilute with ethyl acetate (50 mL), wash the organic phase with saturated brine (3×50 mL), distill off the solvent from the organic phase under reduced pressure, and separate the crude product by column chromatography to obtain 6-phenylimidazo[1,2-a]pyridin-2-amine 1.58 g, with a yield of 75%.

[0029] Example 3

[0030] Dissolve 6-phenylimidazole (19.52 g, 0.10 mol), dichlorodimethylhydantoin (11.82 g, 0.06 mol) and benzenesulfonic acid (0.79 g, 5 mmol) in trifluoroethanol (80 mL) under air. Stir the mixture at 70 °C for 24 hours. After the reaction is complete, cool it to room temperature and distill off most of the organic solvents under reduced pressure. Extract and separate with ethyl acetate (80 mL) and saturated aqueous Na2S2O3 solution (20 mL). Distill off the solvent under reduced pressure. The crude product is separated by column chromatography to obtain 2-chloro-6-phenyl-imidazo[1,2-a]pyridine 16.31 g, with a yield of 71%.

[0031] Under a nitrogen atmosphere, 2-chloro-6-phenyl-imidazo[1,2-a]pyridine (2.30 g, 10 mmol), hexamminenickel(II) chloride (0.81 g, 3.5 mmol), and 2,2'-bipyridine (78.1 mg, 0.5 mmol) were added to a reaction flask. While stirring, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD, 1.99 g, 13 mmol) and DMF (15 mL) were added. The mixture was heated to 90 °C and stirred for 24 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (3 × 50 mL). The solvent was removed from the organic phase by distillation under reduced pressure. The crude product was separated by column chromatography to obtain 1.51 g of 6-phenyl-imidazo[1,2-a]pyridin-2-amine with a yield of 72%.

[0032] Example 4

[0033] 6-Phenyl-imidazole (19.52 g, 0.10 mol), dichlorodimethylhydantoin (11.82 g, 0.06 mol), and benzenesulfonic acid (0.79 g, 5 mmol) were dissolved in hexafluoroisopropanol (80 mL) under air. The mixture was stirred at 90 °C for 24 hours. After the reaction was complete, it was cooled to room temperature, and most of the organic solvent was removed by distillation under reduced pressure. Ethyl acetate (80 mL) was added, and the mixture was extracted and separated with a saturated aqueous Na2S2O3 solution (20 mL). The solvent was removed by distillation under reduced pressure. The crude product was separated by column chromatography to obtain 17.68 g of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine with a yield of 77%.

[0034] Under a nitrogen atmosphere, 2-chloro-6-phenyl-imidazo[1,2-a]pyridine (2.30 g, 10 mmol), hexamminenickel(II) chloride (0.81 g, 3.5 mmol), and 2,2'-bipyridine (78.1 mg, 0.5 mmol) were added to a reaction flask. While stirring, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.98 g, 13 mmol) and DMSO (15 mL) were added. The mixture was heated to 90 °C and stirred for 24 hours. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (50 mL), and the organic phase was washed with saturated brine (3 × 50 mL). The solvent was removed from the organic phase by distillation under reduced pressure. The crude product was separated by column chromatography to obtain 1.41 g of 6-phenyl-imidazo[1,2-a]pyridin-2-amine with a yield of 67%.

[0035] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 6-phenyl-imidazo[1,2-a]pyridin-2-amine compounds, characterized in that, It includes the following steps: Under the catalysis of benzenesulfonic acid, 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin undergo a chlorination reaction to obtain 2-chloro-6-phenyl-imidazo[1,2-a]pyridine; under the action of a base and a bipyridine ligand, 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) dichloride undergo an amination reaction to obtain 6-phenyl-imidazo[1,2-a]pyridin-2-amine.

2. The synthesis method according to claim 1, characterized in that, In the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the catalyst used is benzenesulfonic acid.

3. The synthesis method according to claim 1, characterized in that, In the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the solvent used is one of hexafluoroisopropanol and trifluoroethanol.

4. The synthesis method according to claim 1, characterized in that, In the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the reaction temperature is 40~110 °C, and the reaction time is 12~30 hours.

5. The synthesis method according to claim 1, characterized in that In the chlorination reaction of 6-phenyl-imidazo[1,2-a]pyridine and dichlorodimethylhydantoin, the molar ratio of 6-phenyl-imidazo[1,2-a]pyridine, dichlorodimethylhydantoin and benzenesulfonic acid is 1:(0.5~0.8):(0.03~0.1).

6. The synthesis method according to claim 1, wherein In the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) dichloride, the ligand used is bipyridine.

7. The synthesis method according to claim 1, characterized in that, In the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) dichloride, the base used is one of 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

8. The synthesis method according to claim 1, characterized in that, In the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) dichloride, the solvent used is one of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and acetonitrile.

9. The synthesis method according to claim 1, characterized in that, In the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) dichloride, the reaction temperature is 60~130 °C, and the reaction time is 15~30 hours.

10. The synthesis method according to claim 1, characterized in that, In the amination reaction of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine and hexaamminenickel(II) dichloride, the molar ratio of 2-chloro-6-phenyl-imidazo[1,2-a]pyridine, hexaamminenickel(II) dichloride, bipyridine and the base is 1:(0.35~0.5):(0.05~0.1):(1.0~1.5).

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