4,6-Dichloropyrimidine → HCID 86635140, compound

Participants

Reaction Steps

To a solution of 4,6-dichloropyrimidine (50 g, 0.34 mol, 1.0 equiv) in CH3CN (1.2 L), was added NaHCO3 (34 g, 0.40 mol, 1.2 equiv) and (R)-(−)-2-amino-1-phenyl-ethanol (48.3 g, 0.35 mol, 1.05 equiv) sequentially. The reaction mixture was stirred at reflux temperature under N2 for 3 hours then cooled to rt. HPLC analysis of the crude reaction mixture indicated that the reaction was complete, to afford the intermediate (1R)-2-[(6-chloropyrimidin-4-yl)amino]-1-phenylethanol. In the same flask, without purification or work-up, was added a solution of K3PO4 (85 g, 0.40 mol, 1.2 equiv) in H2O (750 mL), 3-chloro-4-(trifluoromethyl)phenylboronic acid (79.4 g, 0.35 mol, 1.05 equiv), Pd(dppf)Cl2. CH2Cl2 (2.4 g, 2.9 mmol, 0.009 equiv) and Pd(OAc)2 (68 mg, 0.29 mmol, 0.0009 equiv) sequentially under N2 at rt. The reaction solution was degassed with N2 (3×) and was stirred at reflux temperature for 16 hours then cooled to rt. The layers were separated and the CH3CN phase was dried (MgSO4) and filtered. The filtrate solution was stirred with Si-Thiol (8.8 g, 1.5 mmol/g loading, 4 equiv of Pd added) at rt for 1 hour. Si-Thiol is commercially available through SiliCycle (230-400 mesh, 40-63 μm). The Si-Thiol was removed by filtration and washed with EtOAc. The organics were combined and concentrated under reduced pressure. The crude residue was recrystallized from hot EtOH (−250 mL) with stirring to afford the title compound (83 g). Further concentration of the mother liquor followed by a second recrystallization from hot EtOH with stirring provided an additional crop of the title compound (23 g). The combined recrystallized yield of the title compound was 80% (106 g, >99% ee). MS (ESI): mass calcd. for C19H15ClF3N3O, 393.1; m/z found, 394.1 [M+H]+. 1H NMR (CDCl3, 500 MHz): 8.69 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.52-7.28 (m, 5H), 6.74 (s, 1H), 5.42 (brs, 1H), 5.10-4.98 (m, 1H), 3.92 (brs, 1H), 3.70-3.58 (m, 1H).

Provenance & Evidence