Background and overview of the preparation method of 2-bromo-4-methyl-5-nitropyridine
2-Bromo-4-methyl-5-nitropyridine is a pharmaceutical intermediate that can be prepared by nitration of 2-bromo-4-methyl-5-nitropyridine trifluoromethoxypyridine as raw material 4-Methyl-5-nitro-2-aminopyridine, and then 2-bromo-4-methyl-5-nitropyridine is prepared by diazotization reaction. 2-Bromo-4-methyl-5-nitropyridine can be used to prepare GPR receptor agonists such as 1-(1-(5-ethylpyrimidin-2-yl)piperidinyl-4-yl)-5- (4-(methylsulfonyl)phenyl)-1hydro-pyrrolo[2,3-c]pyridine.
Preparation method of 2-bromo-4-methyl-5-nitropyridine
Preparation method of 2-bromo-4-methyl-5-nitropyridine Step 1: 4-methyl-5-nitro-2-aminopyridine
To a solution of 4-methyl-2-aminopyridine (5.80g, 53.6mmol) in concentrated sulfuric acid (8mL) at 5-20°C, slowly add concentrated sulfuric acid (4.00mL, 75mmol) and concentrated nitric acid (4.05mL , 91mmol) mixture. The reaction solution was stirred at room temperature for 30 minutes, then heated to 50°C and stirred for 7 hours. After cooling to room temperature, pour the reaction solution into crushed ice, adjust the pH value to 9 with concentrated ammonia water, and filter. The residue was separated by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain the desired product (1.5 g, 18%). 1HNMR(DMSO‑d6): δ8.75(1H,s), 7.27(2H,s), 6.31(1H,s), 2.49(3H,s).
Preparation method of 2-bromo-4-methyl-5-nitropyridine Step 2: 2-bromo-4-methyl-5-nitropyridine
To a mixture of tert-butyl nitrite (202mg, 1.96mmol), copper bromide (225mg, 1.57mmol) and acetonitrile at 60-6 sodium pyrithione at 5°C, 4-methyl was added in batches -5-nitro-2-aminopyridine (202 mg, 1.96 mmol). The mixture was heated to 70°C and stirred for 2 hours, cooled to room temperature and concentrated in vacuo. Add ethyl acetate and water, collect the organic phase, wash with water and saturated brine in sequence, dry over anhydrous sodium sulfate, and concentrate in vacuo to remove the solvent. The residue was separated by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain the desired product (50 mg, 17%). 1HNMR (CDCl3): δ8.94 (1H, s), 7.53 (1H, s), 2.64 (3H, s).
References
[1][Chinese invention] CN201110034156.8 Bicyclic heteroaryl compounds as GPR receptor agonists and their compositions and applications
