2,6-Dichloro-3-methoxybenzaldehyde synthesis

Yield:6505-37-9 87%

Reaction Conditions:

with potassium carbonate;caesium carbonate in N,N-dimethyl-formamide at 20;

Steps:

46

Preparation 46; 2,6-Dichloro-3-methoxy-benzaldehyde; Dissolve 2,4-dichloro-phenol (30 g, 184 mmol) and cool to 0⁰C. Add imidazole(28 g, 405 mmol) followed by t-butyldimethylsilyl chloride (3 Ig, 202 mmol). Warm reaction mixture to room temperature, and stir for 20 minutes. Pour reaction mixture into water and extract with ether. Separate layers and wash organics with water, 2x brine, dry over sodium sulfate, filter and concentrate to yield 48.4 g (95%) of tert-butyl-(2,4- dichloro-phenoxy)-dimethyl-silane.Dissolve tert-Butyl-(2,4-dichloro-phenoxy)-dimethyl-silane (48.4g, 175 mmol) in tetrahydrofuran (575ml) and cool to -78°C. Add sec-butyl lithium (1.4M, 131ml, 183 mmol) slowly at -78°C and stir at -78°C for 30 minutes. Add N,N-dimethylformamide and stir at -78°C for 1.5 hours. Pour reaction mixture into acetic acid in water (1:12, 830 ml) and stir warming to room temperature. Extract with ether, wash with water, brine dry over sodium sulfate, filter and concentrate to yield a mixture of the title compound and EPO TBS protected analog. Slur in hexanes and filter to yield 15g (45%) of 2,6-dichloro-3- hydroxy-benzaldehyde.Dissolve 2,6-dichloro-3-hydroxy-benzaldehyde (10.7 g, 56 mmol) in N,N- dimethylformamide (80 ml), add potassium carbonate (15 g, 112 mmol) , cesium carbonate(18.3 g, 56 mmol), iodomethane (7 ml, 112 mmol) and stir over night at room temperature. Filter reaction mixture into water washing solids with DMF, extract filtrate with ethyl acetate wash with water, brine, dry over sodium sulfate, filter and concentrate to yield 10 g (87%) of 2,6-dichloro-3-methoxy-benzaldehyde.

References:

WO2006/49952,2006,A1 Location in patent:Page/Page column 68-69