2-Chloropyrimidine → HCID 178441569, compound

Temperature

-78 °C

n-BuLi (1.5 M in hexane, 40 mL, 60 mmol) was added dropwise to a cooled solution of 4,5-dibromo-2-tert-butyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (23.6 g, 57.2 mmol) in anhydrous THF (250 mL) at −78° C. After 30 min at −78° C., a solution of 2-chloropyrimidine (7.21 g, 63.0 mmol) in anhydrous THF (2 mL) was added dropwise and the reaction was stirred at −78° C. for 1 h. The reaction was quenched by the addition of saturated aqueous NH4Cl solution and allowed to warm to rt. The mixture was partitioned with EtOAc and the layers separated. The aqueous portion was extracted with EtOAc (3×) and the combine organic layers were washed with water, brine, dried (MgSO4), and concentrated. The resulting residue was dissolved in dry EtOAc, treated with MnO2 (5.2 g, 60 mmol), and heated to reflux for 3 h. The reaction was allowed to cool to rt and filtered through Celite. The filter cake was washed thoroughly with EtOAc and the combine filtrates were concentrated. The remaining residue was purified by flash chromatography (SiO2, 100:0-90:10 hexanes-EtOAc) to give 10 g (37%) of 4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)-2-chloropyrimidine: LCMS (m/z): 447.10 (MH+), tR=1.30 min. 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J=5.3 Hz, 1H), 7.83 (d, J=5.3 Hz, 1H), 5.85 (s, 2H), 3.45 (m, 2H), 0.76 (m, 2H), −0.08 (s, 9H).

1. customThe reaction was quenched by the addition of saturated aqueous NH4Cl solution
2. temperatureto warm to rt
3. customThe mixture was partitioned with EtOAc
4. customthe layers separated
5. extractionThe aqueous portion was extracted with EtOAc (3×)
6. washthe combine organic layers were washed with water, brine
7. dry with materialdried (MgSO4)
8. concentrationconcentrated
9. dissolutionThe resulting residue was dissolved in dry EtOAc
10. temperatureheated
11. temperatureto reflux for 3 h
12. temperatureto cool to rt
13. filtrationfiltered through Celite
14. washThe filter cake was washed thoroughly with EtOAc
15. concentrationthe combine filtrates were concentrated
16. customThe remaining residue was purified by flash chromatography (SiO2, 100:0-90:10 hexanes-EtOAc)

ORD record

ord-a72d4f11be3b41c1a70d1fe8011317b4

Source dataset

uspto-grants-2014_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08865732B2