Preparation of 3,5-dimethylpyridin-2-amine_Industrial additives

Preparation background and overview of 3,5-dimethylpyridin-2-amine

3,5-Dimethylpyridin-2-amine can be used as a pharmaceutical synthesis intermediate.

Preparation of 3,5-dimethylpyridin-2-amine

The preparation of 3,5-dimethylpyridin-2-amine is as follows:

Step 1): 3,5-dimethylnitropyridine-N-(2,4,4-trimethylpentan-2-yl)pyridin-2-amine

To a solution of 3,5-pyridine N-oxide (5g, 40.6mmol) in dichloromethane (120mL), add diisopropylamine (26.6mL, 152mmol), tert-octylamine (2,4,4 -trimethylpentan-2-amine) (8.15 mL, 50.8 mmol) and bromo-tris-pyrrolidine-phosphonium hexafluorophosphate (24.61 g), 52.8 mmol). The mixture was stirred at room temperature for 18 hours under nitrogen. Additional bromo-tris-pyrrolidinyl-hexafluorophosphate (24.61 g, 52.8 mmol) and diisopropylamine (26.6 mL, 152 mmol) were added and the reaction mixture was stirred for 4 days. Sodium carbonate solution and dichloromethane were then added and the organic layer was separated using a phase separator cartridge. The solvent was removed in vacuo and the crude product was purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The title compound (4.98g) was a yellow oil. LCMS (2 min, high pH) Rt 1.64 min, m/z (ES+) 235 (M+H).

Step 2): 3,5-dimethylpyridin-2-amine

3,5-Dimethyl-N-(methoxypyridine 2,4,4-trimethylpentan-2-yl)pyridin-2-amine (6.5g, 27.7mmol) was mixed with 2, 2,2-Trifluoroacetic acid (46 mL, 621 mmol) was heated to 50°C. 4.5 hours. The mixture was concentrated in vacuo and diluted with dichloromethane (10 mL) and water (10 mL). The layers were separated and the aqueous phase was neutralized to pH 7-8 using saturated bicarbonate solution. The product was then extracted with dichloromethane (3 × 10 mL) and the organics were dried using a phase separator cartridge. The solvent was evaporated in vacuo. The title compound, 3,5-dimethylpyridin-2-amine (2.99 g), was a white solid. LCMS (2 min, high pH) Rt 0.69 min, m/z (ES+) 123 (M+H).