Phosphorus oxychloride → 6-Chloro-2-methylpyrimidin-4-amine

Participants

Reaction Conditions

Reaction Steps

6-Amino-2-methylpyrimidin-4-ol (5 g) was suspended in phosphorous oxychloride (50 ml) and heated at 80° C. for 1 hour. A few drops of DMF was added and the reaction heated to 105° C. for 3 hours to give an orange solution. The reaction was cooled, concentrated in vacuo and azeotroped with toluene. The residue was cautiously partitioned between ethyl acetate and ice-cold saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried and concentrated in vacuo to afford 6-chloro-2-methylpyrimidin-4-amine as a yellow solid which was used without further purification (3 g, 68%); NMR Spectrum (300 MHz, CDCl3) 2.50 (s, 3H), 5.00 (br s, 2H), 6.30 (s, 1H); Mass Spectrum MH++CH3CN 185. 6-Chloro-2-methylpyrimidin-4-amine (2.45 g) was suspended in 1-methylpiperazine (24 ml) and the reaction heated at 140° C. for 20 minutes in a microwave reactor. The reaction was cooled and concentrated in vacuo. The residue was dissolved in methanol and neutralised with polymer-bound carbonate resin for 1 hour, then filtered and concentrated to give an orange solid that was triturated with ethyl acetate to give 2-methyl-6-(4-methylpiperazin-1-yl)pyrimidin-4-amine as a cream solid (2.64 g, 81%); NMR Spectrum (300 MHz, CDCl3) 2.20 (s, 3H), 2.30 (s, 3H), 2.40 (m, 4H), 3.50 (m, 4H), 4.40 (br s, 2H), 5.40 (s, 1H); Mass Spectrum MH+ 208.

Provenance & Evidence