2-Amino-4-methylphenol → 2-{2-[3-(5-Cyano-pyrazin-2-yl)-ureido]-4-methyl-phenoxymethyl}-morpholine-4-carboxylic acid tert-butyl ester

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Reaction Steps

2-(2-Amino-4-methyl-phenoxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (0.087 g, 0.270 mmol) was prepared from 2-amino-4-methyl-phenol according to methods of Compound 3, Steps 1 and 2 using 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (prepared according to the procedure for Compound 2, Step 1 using the corresponding acid) and 4-methyl-2-nitro-phenol. It was combined with triphosgene (0.029 g, 0.10 mmol), toluene (2 mL) and Hunig's base (0.15 mL, 0.86 mmol), and stirred at room temperature for 25 min. The suspension then was transferred through a cannula to a cold solution (−78° C.) containing 5-amino-pyrazine-2-carbonitrile (0.032 g, 0.27 mmol), and lithium bis(trimethylsilyl)amide (0.27 mmol) in THF (1 mL), which had been stirring at −78° C. for 30 min. The reaction was allowed to warm, then was stirred for 16 h at room temperature. A precipitate formed and was collected by filtration to yield the desired product (0.043 g).

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