ethyl 3-(2-bromo-6-chlorophenyl)propanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 3-(2-bromo-6-chlorophenyl)propanoate (Example 1f), 5.0 g, 17.1 mmol) and sodium cyanide (0.168 g, 3.43 mmol) were stirred in methanamine (8 M in ethanol, 30 mL, 240 mmol) at rt overnight. The solvent was evaporated, the residue was taken up in ethyl acetate and the mixture was washed with saturated aqueous sodium carbonate and brine. The organic phase was separated and the solvent was removed by rotary evaporation. The crude product was added to a silica gel column and was eluted with 0-100% ethyl acetate in heptane. The collected fractions were combined and the solvent was removed by rotary evaporation to give the title product. Yield 2.98 g, 63%. 1H NMR (500 MHz, CDCl3) δ ppm 2.40-2.47 (m, 2H) 2.85 (d, 3H) 3.28-3.35 (m, 2H) 5.44 (br. s., 1H) 7.02 (t, 1H) 7.33 (dd, Hz, 1H) 7.47 (dd, Hz, 1H). MS m/z 277.9 [M+H]+. The solvent was evaporated the mixture was washed with saturated aqueous sodium carbonate and brine The organic phase was separated the solvent was removed by rotary evaporation The crude product was added to a silica gel column was eluted with 0-100% ethyl acetate in heptane the solvent was removed by rotary evaporation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl 2-(2-bromo-6-chlorobenzyl)malonate (13.0 g, 35.7 mmol), water (1.29 mL, 71.5 mmol) and lithium chloride (3.03 g, 71.50 mmol) in dimethylsulfoxide (75 mL) were heated to +185° C. for 1 h. The solution was allowed to cool. 75 mL of water was added. The mixture was extracted with ethyl acetate. The organic phase was washed with water and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered and the solvent was removed by rotary evaporation to give the title compound. Yield: 7.34 g, 70%. 1H NMR (500 MHz, CDCl3) δ ppm 1.27-1.30 (m, 3H) 2.55-2.61 (m, 2H) 3.27-3.33 (m, 2H) 4.16-4.21 (m, 2H) 7.02 (t, 1H) 7.31-7.35 (m, 1H) 7.45-7.50 (m, 1H). MS m/z 293.0 [M+H]+. to cool The mixture was extracted with ethyl acetate The organic phase was washed with water and aqueous NaHCO3 The organic phase was separated dried over MgSO4 filtered the solvent was removed by rotary evaporation