Imidazo[1,2-a]pyrazine

Imidazo[1,2-a]pyrazine is an imidazopyrazine, a polycyclic heteroarene and an azaarene.

Pyrazin-2-amine 4a (5 g, 52 mmol) was dissolved in a 40percent 2-chloroacetaldehyde solution (15 mL, 78 mmol), followed by addition of sodium bicarbonate (6.60 g, 78 mmol). Step 1 A mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50percent in water, 50 ml, 394 mmole) and NaHCO5, 6 , 7 , 8-tetrahydroimidazo [1, 2-a] pyrazine A29Stage 1. was added to a mixture of 2-aminopyrazin (25 g, 262.9 mmole), chloroacetaldehyde (50percent in water, 50 ml, 394 mmole) and NaHCOA mixture of 2-aminopyrazine (25 g, 262.9 mmol) and chloroacetaldehyde (50percent solution in water, 50 ml, 394 mmol) was heated for 2 d at 100° C. in the presence of sodium hydrogen carbonate (33.1 g, 394 mmol). The reaction mixture was cooled to room temperature, and saturated potassium carbonate solution (100 ml) was added thereto. Extraction with dichloromethane was then carried out, and the organic phase was dried (NaImidazo[1, 2-aJpyrazine: A solution of aminopyrazine (1 g, 10.5 mmol) and chloroacetaldehyde (50percent wt in H, O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated at 90°C5 in a sealed tube for 5 h. Upon cooling to ambient temperature, the reaction mixture was concentrated and diluted with dichlorornethane (DCM). The organic layer washed with saturated aqueous NaHCO3 then dried over MgSO4 and concentrated. The crude product was purifiedsilica gel flash chromatography (eluted with 10percent MeOH/DCM) to provide 0.8 g of product.To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48percent, 26.5 ml). 2-Pyrazinamine (9.51 g, 100 mmol) was dissolved in ethanol (300 ml) and 2-bromo- 1 , 1-bis(ethyloxy)ethane (21.06 ml, 140 mmol) was added. 48percent hydrobromic acid (33.3 ml) was added and the mixture heated at reflux for 24 hr. The solution was concentrated in vacuo to a crude solid that was basified with 10percent ammonia-ice (300ml). The solution was extracted in to ethyl acetate (3 x 300ml), the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid, (4.76g). The solid was purified by flash chromatography (Biotage SP4, 40+M, eluting with a 0-100percent [25percent 2M ammonmia/methanol in dichloromethane] in dichloromethane gradient) to afford imidazo[1 , 2-a]pyrazine (2.86 g, 24.01 mmol, 24.01 percent yield).).2-amino-pyrazine (10g, 0.1mmol) was dissolved in 150ml of absolute ethanol, and slowly added dropwise to the above solution chloroacetaldehyde dimethylacetal (18.7g, 0.15mmol), then added dropwise 37percent of concentrated hydrochloric acid, the pH of the reaction system is 3-4, after completion of the dropwise addition, the reaction system was heated to 70-80 , TLC detection progress of the reaction, 12 hours after the completion of the reaction, the reaction solution was cooled to room temperature, is added 1N sodium hydroxide solution to adjust the pH value of the reaction system to 8-9, then adding a mixed solvent of 200ml of isopropanol and methylene chloride (wherein the isopropanol / dichloromethane 1/5 volume ratio) was extracted, and extracted twice , the combined organic phases were dried over anhydrous sodium sulfate, filtered, dried organic solvent was spin-indole [1, 2-A] pyrazine 11g, yield of about 90percent2-Aminopyrazine (100 mg, 1.1 mmol) and bromoacetaldehyde dimethylacetal (253 mg, 1.6 mmol) were dissolved in ethanol (4.5 ml), hydrobromic acid (48percent, 0.5 ml) added and the mixture was heated under reflux for 18 h. To a solution of 2-aminopyrazine (2.0 g, 21.03 mmol) in ethanol (40 mL) was added 2-bromo-1, 1-dimethoxyethane (2.5 mL, 21.03 mmol) followed by 5 drops of concentrated hydrochloric acid. After refluxing for 14 hours, the solvent was evaporated. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (100percent ethyl acetate, 10percent methanol in ethyl acetate, then 10percent methanol in dichloromethane) to give 536 mg of the title compound as a solid. 2-Aminopyrazine (500 mg, 5.26 mmol) was dissolved in ethanol (25 mL), and bromoacetaldehyde dimethyl acetal (0.93 mL, 7.89 mmol) and 40percent hydrobromic acid (3 mL) were added thereto. Heat to reflux overnight.After completion of the reaction, it was cooled to room temperature, and a 1N aqueous sodium hydroxide solution (20 mL) was added thereto.Extracted with 20percent isopropanol / dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated.The residue was purified by silica gel column chromatography to give a white solid420mg.Synthesis of Imidazo[1, 2-a]pyrazine-Intermediate C To a solution of aminopyrazine (5 g, 53 mol, 1 eq.) in ethanol (212 ml) was added bromoacetaldehyde diethylacetal (12 ml, 80 mol, 1.5 eq.) and HBr (48%, 26.5 ml). The mixture was heated at 70-80 C. for 17 hours. The mixture was then cooled to rt (room temperature), then a mixture of 1N NaOH (200 ml) and 20% IPA/DCM (isopropyl alcohol/Dichloromethane) was added to the reaction mixture. The combined organic layer was dried over sodium sulfate and concentrated to afford 5.9 g of brown solid of General procedure: Imidazo[1, 2-a]pyrazines (0.3 mmol), 2-chlorobenzaldehyde (0.33 mmol, 1.1 equiv.), K2CO3 (0.9 mmol, 3 equiv.), PivOH (30 mol%), Pd(OAc)2 (7.5 mol %), and Xantphos (15 mol %) were added to a 10 mL round-bottomed flask, and then a mixed solvent of 3 mL of DMF and 30 uL of H2O was added. The mixture was stirred under air at 110 C for 24 h. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using dichloromethane/methanol as the eluent to give the pure product.General procedure: Imidazo[1, 2-a]pyrazines (0.3 mmol), 2-chlorobenzaldehyde (0.33 mmol, 1.1 equiv.), K2CO3 (0.9 mmol, 3 equiv.), PivOH (30 molpercent), Pd(OAc)2 (7.5 mol percent), and Xantphos (15 mol percent) were added to a 10 mL round-bottomed flask, and then a mixed solvent of 3 mL of DMF and 30 uL of H2O was added. The mixture was stirred under air at 110 °C for 24 h. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate three times. The combined organic layer was dried with anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using dichloromethane/methanol as the eluent to give the pure product.2-amino-pyrazine (10g, 0.1mmol) was dissolved in 150ml of absolute ethanol, and slowly added dropwise to the above solution chloroacetaldehyde dimethylacetal (18.7g, 0.15mmol), then added dropwise 37% of concentrated hydrochloric acid, the pH of the reaction system is 3-4, after completion of the dropwise addition, the reaction system was heated to 70-80 , TLC detection progress of the reaction, 12 hours after the completion of the reaction, the reaction solution was cooled to room temperature, is added 1N sodium hydroxide solution to adjust the pH value of the reaction system to 8-9, then adding a mixed solvent of 200ml of isopropanol and methylene chloride (wherein the isopropanol / dichloromethane 1/5 volume ratio) was extracted, and extracted twice , the combined organic phases were dried over anhydrous sodium sulfate, filtered, dried organic solvent was spin-indole [1, 2-A] pyrazine 11g, yield of about 90%

Molecular Weight:119.12
XLogP3:0.7
Hydrogen Bond Acceptor Count:2
Exact Mass:119.048347172
Monoisotopic Mass:119.048347172
Topological Polar Surface Area:30.2
Heavy Atom Count:9
Complexity:105
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes