Application of 4-bromo-2-trifluoromethyl benzyl ether_Kain Industrial Additive

Overview^[1][2]

4-Bromo-2-trifluoromethyl benzyl ether is an ether organic compound that can be used as a pharmaceutical synthesis intermediate.

Preparation^[1]

1) 4-bromo-2-(trifluoromethyl)phenol

Put 2-(trifluoromethyl)phenol (1.7g, 10.49mmol)/10mLCH2Cl2 into a round-bottomed flask with a stirring rod, and cool to 0°C. Bromine (0.540ml, 10.49mmol)/2mLCH2Cl2 was added dropwise. The reaction mixture was stirred at 0°C for 1 hour and then allowed to warm to ambient temperature over 1 hour. Aqueous NaHSO3 was added and the mixture was extracted with CH2Cl2. The organic phase was washed with aqueous NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography eluting with 100% CH2Cl2 to give the title compound.

1HNMR (300MHz, dimethyl sulfoxide-d6) δppm10.90 (s, 1H), 7.63 (m, 1H), 6.98 (d, 1H).

2) 4-Bromo-2-trifluoromethyl benzyl ether

A round-bottomed flask with a stirring rod was charged with 4-bromo-2-(trifluoromethyl)phenol (1.5g, 6.22mmol), Cs2CO3 (6.08g, 18.67mmol) and benzyl bromide (0.813ml, 6.85 mmol)/15mLN, N-dimethylformamide. The mixture was stirred at ambient temperature for 16 hours, diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate/hexane to give the title compound 4-bromo-2-trifluoromethylbenzyl ether. MS(ESI(+))m/e331.0(M+H)+.

Apply^[1]

4-Bromo-2-trifluoromethyl benzyl ether can be used as a pharmaceutical synthesis intermediate. For example, prepare 2-(4-(benzyloxy)-3-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane : A 100mL round bottom flask is filled with 4-bromo-2-trifluoromethyl benzyl ether (1.90g, 5.74mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl Base-2,2'-bis(1,3,2-dioxaborane) (1.75g, 6.89mmol), [1,1'-bis(diphenylphosphino)diocene Iron] dichloropalladium(II) dichloromethane (0.234g, 0.287mmol), diphenylphosphinoferrocene (0.159g, 0.287mmol) and potassium acetate (1.689g, 17.21mmol)/50mL Oxane. The mixture was degassed with N2 and heated at 80°C overnight, diluted with water, and extracted into ethyl acetate. The organic layer was washed with brine and dried (MgSO4), filtered, and concentrated. The crude product was purified on silica gel eluting with 0-10% ethyl acetate/hexane to give the title compound.

MS(DCI(+))m/e396(M+NH4)+; 1HNMR(300MHz, dimethyl sulfoxide‑d6) δppm7.64(dd, 1H), 7.56‑7.16(m, 7H), 5.26 (s, 2H), 1.29 (s, 12H).

Main reference materials

[1] CN201080033864.3 Pyrimidine inhibitors of kinase activity