preparation of 2-chloropyrimidine-4-boronic acid_industrial additives

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