6,8-Dibromoimidazo[1,2-a]pyrazine

To an aqueous (10 kg) solution of 3, 5-dibromopyrazine-2-amine (1018 g, 4.03 mol), 2-bromo-1, 1-dimethoxyethane (1.79 kg, 4.14 mol) was added at room temperature and stirred for 2 hours while heating under reflux. To the reaction solution, water (15.3 kg) and sodium hydrogen carbonate (744 g) were added and further stirred for 15 minutes. The resultant solid substance was obtained by filtration to obtain the titled compound (1106 g, 3.99 mmol, 99percent) as a brown solid substance.1H-NMR (400 MHz, DMSO-dGeneral Procedures; 6, 8-Dibromo-imidao[1, 2-a]pyrazine; A mixture of 2-Amino-3, 5-dibromopyrazine (72.0 g, 285 mmol) in ethanol (1.1 L) was stirred at room temperature and treated with bromoacetaldehyde diethylacetal (97 mL, 640 mmol), water (72 mL) and concentrated hydrobromic acid (72 mL). The reaction was heated at reflux for five hours, then cooled slowly to room temperature over 16 hours. The resulting white precipitate was then filtered, resuspended in dichloromethane (2 L) and basified with aqueous sodium carbonate solution. After vigorous mixing, the organic phase was separated, dried over MgS04 and concentrated in vacuo, to give a pale yellow solid. Purification of the crude solid was achieved by suspending it in diisopropyl ether (500 mL) and stirring vigorously for one hour. The resulting suspension was filtered to give the title compound (A) as a pale yellow solid (74.5 g, 95 percent).A 100-mL, three-neck flask was charged with 2-bromo-l, l-dimethoxyethane 4 (23.2 g (16 mL, 137.2 mmol) and aqueous HBr (47.6percent HBr by wt, 8.8 mmol/mL, 6.6 mL, 58.8 mmol), and the reaction mixture was heated to reflux (55°C) for 2 hours. The mixture was allowed to cool to 40°C, and solid NaHCC3 was added in small portions, until evolution of gas ceased. The resulting suspension was filtered, under vacuum, into a 500-mL, three-neck flask, and the filter cake was washed with isopropanol (200 mL). Solid 3, 5-dibromopyrazin-2-amine (3) (12.0 g, 47.2 mmol) was added into the isopropanol filtrate, and the reaction mixture was heated at reflux (78°C) for 16 hours. The resulting suspension was cooled to room temperature, filtered, the cake was washed with cold isopropanol (100 mL), and then the cake was dried under vacuum. The cake was transferred into a three-neck flask, into which, water (200 mL) was added, followed by solid KIntermediate -1 : Preparation of 6, 8-dibromo-imidazo[ 1 , 2-a]pyrazineTo a stirred suspension of 2-amino-3, 5-dibrompyrazine (427 g, 1688mmol) in water (6.4 L) / THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C to yield 6, 8-dibromo-imidazo[1 , 2-a]pyrazine as an off-white solid (500 g, 107percent with residual MeOH): 3, 5-dibromo-pyrazin-2-ylamine (10.4g, 41.12 mmol), and bromoacetaldehyde diethyl acetal (9.8 ml, 62.51mmol) then dissolved in a mixed solvent of tetrahydrofuran (14 ml) and distilled water (140 ml), and the mixture was stirred for 4 hours at 120°C , in addition stirred at room temperature for 12 hours to.Saturated aqueous sodium hydrogen carbonate solution to the reaction solution was neutralized by addition.The resulting solid was filtered, washed with distilled water and dried to give the title compound (8.7g, 76percent).To a stirred suspension of 2-amino-3, 5-dibrompyrazine (427 g, 1688mmol) in water (6.4 L) / THF (482 mL), at rt was added bromacetaldehyde-diethylacetal (998 g, 5065 mmol) in one portion. After stirring under reflux for 4 h, the clear orange solution was stirred for an additional 15 h at rt. The suspension was filtered, and the remaining solid was washed with MeOH (2 L) and dried in vaccuo at 60° C to yield 6, 8-dibromo-imidazo[1 , 2-a]pyrazine as an off-white solid (500 g, 107percent with residual MeOH): To a 1000 mL single-necked round bottom flask was added 2-amino-3, 5-dibromopyrazine (43.18 g, 220 mmol), chloroacetaldehyde (77.72 g, 396 mmol) and DMF 550 mL. The mixture in the reaction flask was stirred at 80 ° C for 8.5 hours. TLC and GC confirmed the reaction was complete. After the reaction was completed, the solvent was removed by rotary evaporation to give a crude product, which was purified by silica gel column chromatography to obtain the pure product 6, 8-dibromoimidazo [1, 2a] pyrazine. After drying, the yield was 83.71percent and the purity was 99.00percent (HPLCA mixture of 2-amino-3, 5-dibromopyrazine (Aldrich, 6.0 g, 24.0 mmol) and 50percent aqueous solution of chloroacetaldehyde (Aldrich, 4.8 mL) in 2-propanol (30 mL) was stirred and refluxed under N2 for 24 hr. CH2Cl2 (300 mL) and triethylamine (12 mL) were added and the solvent was evaporated. The residue was suspended in 10:1 H2O:2-propanol (200 mL), filtered, and the solid was washed on filter with 10:1 H2O:2-propanol (2.x.100 mL). It was dried in a vacuum to yield pale beige solid (4.81 g, 74percent).Step-(ii): Synthesis of 6, 8-dibromoimidazo [1, 2-a] pyrazine:To a stirred solution of Intermediate-lOa (0.2 g, 0.79 mmol) in IPA (5niL) was added Chloro acetaldehyde (0.12 mL, 0.952 mmol), and stirred at 100°C for 24h. After the reaction was completed, the reaction mixture was cooled RT, pale brown solid was precipitated out, filtered the solid dried under vaccum to get the desired product (150 mg, 53percent); 1H NMR (400 MHz, DMSO-d6): ö 9.02(s, 1H), 8.24(s, 1H), 7.9(s, 1H); MS (ES) m/z 277.9 (M+1).

6,8-Dibromoimidazo[1,2-a]pyrazine is a imidazopyrazine derivative with uterine-relaxing, antibronchospastic, and cardiac-stimulating properties. 6,8-Dibromoimidazo[1,2-a]pyrazine also displays theophylline-like properties.

Molecular Weight:276.92
XLogP3:2.7
Hydrogen Bond Acceptor Count:2
Exact Mass:276.86732
Monoisotopic Mass:274.86937
Topological Polar Surface Area:30.2
Heavy Atom Count:11
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes