Preparation background and overview of 2-chloropyrimidine-4-boronic acid
2-Chloropyrimidine-4-boronic acid is an organic intermediate commonly used in Suzuki and other metal coupling reactions. There are reports in the literature that 2-chloropyrimidine-4-boronic acid can be used to synthesize EGFR and ERK kinase inhibitors. EGFR is a member of the erbB (type I) subfamily of RTKs, along with erbB-2, erbB-3, and erbB-4. These receptors are activated by ligands that induce their dimerization, and although EGFR-EGFR homodimers are commonly used for signaling, a more common process in this family is ligand-induced heterodimerization, allowing the signaling entity to This would be, for example, EGFR:erbB-2 or erb-B2:erbB-3 and an appropriate ligand.
Preparation and application of 2-chloropyrimidine-4-boronic acid
2-Chloropyrimidine-4-boronic acid can be used to synthesize the EGFR kinase inhibitor intermediate 2-chloro-4-(1-methylimidazo[1,5-a]pyridin-3-yl)pyrimidine
1) Add N-bromosuccinimide (3.76g, 20m mol of chloropyridine) portionwise to 1-methylimidazo[1,5-a] stirred at 0°C under N Pyridine (2.642 g, 20 mmol) was dissolved in CH2Cl2 (50 mL) and the solution was stirred at room temperature for 2 hours. The reaction mixture was poured onto dilute sodium sulfite solution (0.2M, 50 mL) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×25mL) and the combined organic phases were washed with water (2×25mL), saturated brine (25mL) and dried (MgSO4) . The solvent was removed under reduced pressure and the residue was chromatographed on holmium silicocarbonate gel eluting with EtOAc/hexane to give 3-bromo-1-methylimidazo[1,5-a]pyridine.
2) Dissolve 3-bromo-1-methylimidazo[1,5-a]pyridine (4.223g, 20mmol) and 2-chloropyrimidine-4-boronic acid (3.167g, 20mmol) in DMF (100mL) in K3PO4 (8.48g, 40mmol), tri-o-tolylphosphine (6.09g, 2mmol) and Pd(dba) (0.916g) at 80℃ , 1.0 mmol) and heated together for 12 hours. The reaction mixture was poured onto water (250 mL) and extracted with EtOAc (3×50 mL), washed with water (2×50 mL) and saturated brine (50 mL), dried (NaSO4), and dried in The solvent was removed under reduced pressure. The remaining solid was purified by silica gel chromatography eluting with EtOAc/hexane to give 2-chloro-4-(1-methylimidazo[1,5-a]pyridin-3-yl)pyrimidine.
References
[1] [Invented in China] CN201780016875.2 Selective inhibitor of clinically important mutants of EGFR tyrosine kinase
