Synthesis
The general procedure for the synthesis of 5-bromo-4-chloro-6-methyl-2-pyrimidinamine from 2-amino-4-chloro-6-methylpyrimidine is as follows:
Example 6: Synthesis of 5-bromo-4-chloro-6-methylpyrimidin-2-amine
1. To a solution of 2-amino-4-chloro-6-methylpyrimidine (5.00 g, 34.8 mmol) in dichloromethane (240 mL) was slowly added bromine (1.88 mL, 36.6 mmol).
2. The reaction mixture was stirred at room temperature for 1.5 hours to form a suspension.
3. After the reaction was complete, the reaction mixture was diluted with dichloromethane (1.3 L).
4. The organic phase was washed sequentially with saturated sodium bicarbonate solution (2 x 200 mL) and brine (200 mL).
5. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated to give 5-bromo-4-chloro-6-methylpyrimidin-2-amine (7.5 g, 97% yield).
Product Characterization:
LCMS (M + H): 223
1H NMR (400 MHz, chloroform-d) δ ppm: 2.54 (s, 3H), 5.10 (s, 2H)
References
[1] Patent: WO2008/32162, 2008, A1. Location in patent: Page/Page column 62-63
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 15, p. 5098 - 5103
[3] Journal of Medicinal Chemistry, 2016, vol. 59, # 17, p. 8082 - 8093
[4] Patent: US2018/215720, 2018, A1. Location in patent: Paragraph 0057; 0059; 0074
[5] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 637 - 646
