Nitrogen → Ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate

Participants

Reaction Conditions

Reaction Steps

A mixture of Cs2CO3 (62.1 g, 191 mmol), 5-bromo-N,N-dimethylpyrimidine-2-carboxamide (SM-2: 24 g, 104 mmol) and ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 20 g, 91 mmol); 1,10-phenanthroline (1.64 g, 9.07 mmol) and copper iodide (864 mg, 4.54 mmol) in dimethylformamide (200 ml) was purged with N2 gas and then heated to 90° C. using a mechanical stirrer. The heterogeneous reaction mixture was stirred at this temperature for 18 hours. HPLC indicated near completion. The reaction mixture was cooled to 35° C. and diluted with ethyl acetate (300 ml). The mixture was filtered to remove any cesium carbonate. The filtrate was then partitioned between water (500 ml) and ethyl acetate (500 ml); however, no separation was observed. Concentrated HCL (20 ml) was added to the mixture. When the aqueous phase was about pH1, the phases separated. The organics were separated and the aqueous layer reextracted with ethyl acetate (2×500 ml). All organics were combined and back extracted with water (200 ml) and brine (500 ml). The organics were separated and treated with activated charcoal (10 g) and magnesium sulfate. The mixture was allowed to stir for 10 minutes and then filtered through a plug of celite to afford a crude yellow solution. The filter cake was washed with ethyl acetate (100 mL). The organics were concentrated in vacuo to afford a crude solid this was dried under high vacuum for 4 days. The dry crude solid was triturated using methanol (80 mL). The solids were dispersed into a fine light orange crystalline powder with a red liquor. The solids were isolated by filtration and rinsed with methanol (20 mL). The solid was dried in the vacuum oven at 55° C. for 12 hours to afford ethyl 4-(2-(dimethylcarbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-2a) as a yellow solid (18.2 g, 54%)

Provenance & Evidence