5-AMINO-4-BROMOPYRIMIDINE

591-55-9

849353-34-0

General procedure for the synthesis of 5-amino-4-bromopyrimidine from 5-aminopyrimidine: 1. 5-amino-4,6-dichloropyridine (5.0 g, 30.5 mmol) was dissolved in 250 mL of diethyl ether, to which was added sodium hydroxide solution (20.0 g, 0.50 mol, dissolved in 60 mL of water) and palladium catalyst (10% carbon-loaded palladium, 400 mg). 2. The mixture was placed in a Parr shaker and the reaction was shaken at room temperature under 50 psi hydrogen pressure for 20 hours. 3. Upon completion of the reaction, the mixture was filtered through a CELITES filter aid to separate the organic and aqueous phases. The aqueous phase was extracted with three 100mL portions of ethyl acetate. 4. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuum. The crude product was crystallized from ethyl acetate to give pyrimidin-5-ylamine as a white crystalline solid (2.8 g, 95% yield). 5. The bromination of pyrimidin-5-ylamine was carried out under the same conditions as for the preparation of 4-amino-3-bromo-2,6-dimethylpyridine. The crude product (300 mg, 35% yield) obtained was of sufficient purity to be used without further purification. Alternative synthetic method: 1. 4,6-Dichloro-5-aminopyrimidine (21 g, 128 mmol) was dissolved in 250 mL of methanol and ammonium formate (45 g, 714 mmol) and palladium catalyst (10% carbon-loaded palladium, 1 g, 0.943 mmol) were added sequentially at 0°C. 2. The mixture was stirred at room temperature overnight and after completion of the reaction was filtered through a CELITEO filter aid. 3. The filtrate was concentrated to give a yellow solid to which 100 mL of water and 250 mL of ethyl acetate were added. The organic phase was separated and the aqueous phase was extracted with eight 250mL of ethyl acetate. 4. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuum to give off-white crystals (8.1 g, 67%). 5. 5-Aminopyridine (3.0 g, 31.5 mmol) was dissolved in 150 mL of dichloromethane and 30 mL of methanol and cooled to 0°C. Benzyltrimethylammonium tribromide (13.5 g, 34.7 mmol) was added in batches over 10 min. 6. Stirring was continued at 0 °C for 15 min and then at room temperature for 90 min. The reaction mixture was adjusted to pH 8 with aqueous sodium bicarbonate. 7. The organic layer was separated and the aqueous layer was extracted with three 30 mL of ethyl acetate. The organic extracts were combined, dried with sodium sulfate, filtered and concentrated in vacuum to give an off-white solid (2.8 g, 51%) of sufficient purity to be used without further purification.