5-Bromo-4-chloro-2-methylsulfanyl-pyrimidine

Chemical Properties

White solid

Uses

5-Bromo-4-chloro-2-(methylthio)pyrimidine serves as a starting material for amine intermediates: treatment with ethyl 2-(diphenylmethyleneamino)acetate followed by acid-catalyzed hydrolysis gives the corresponding amine, and SNAr displacement of its chloride affords an intermediate that undergoes Suzuki–Miyaura coupling with a lithium trihydroxy borate salt of 2-pyridinyl compounds[3-4].

Synthesis

Step 3, Preparation of 5-bromo-4-chloro-2-methylthiopyrimidine: 5-bromo-2-(methylthio)pyrimidin-4(3H)-one (110 g) was dissolved in pyridine (400 g) and heated to 80°C. Phosphorus trichloride (100 g) was added dropwise with stirring. After the dropwise addition, the reaction temperature was maintained and stirring was continued for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and subsequently placed in an ice bath. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution and then extracted with ethyl acetate (500 mL). The organic phase was dried with anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was recrystallized by a solvent mixture of petroleum ether and ethyl acetate (1:3, v/v) to give a pale yellow solid powder (98 g) in 83% yield.

References

[1] Patent: CN107488175,  2017,  A. Location in patent: Paragraph 0008; 0010
[2] Acta Chemica Scandinavica, Series B:  Organic Chemistry and Biochemistry,  1982,  vol. 36,  # 1 B,  p. 15 - 18
[3] Rej, R. K., Wang, C., Lu, J., Wang, M., Petrunak, E., Zawacki, K. P., McEachern, D., Yang, C.-Y., Wang, L., Li, R., Chinnaswamy, K., Wen, B., Sun, D., Stuckey, J. A., Zhou, Y., Chen, J., Tang, G., Wang, S. (2021). Discovery of EEDi-5273 as an Exceptionally Potent and Orally Efficacious EED Inhibitor Capable of Achieving Complete and Persistent Tumor Regression. Journal of Medicinal Chemistry, 64(19), 14540–14556. https://doi.org/10.1021/acs.jmedchem.1c01059
[4] Zhang, W., Zhang, D., Stashko, M. A., DeRyckere, D., Hunter, D., Kireev, D., Miley, M. J., Cummings, C., Lee, M., Norris-Drouin, J., Stewart, W. M., Sather, S., Zhou, Y., Kirkpatrick, G., Machius, M., Janzen, W. P., Earp, H. S., Graham, D. K., Frye, S. V., Wang, X. (2013). Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase Inhibitors. Journal of Medicinal Chemistry, 56(23), 9683–9692. https://doi.org/10.1021/jm401387j