Reaction Steps
3-Benzyloxycarbonylamino-6-phenylpyrid-2-one (1.7 g) was added to a suspension of NaH (0.14 g) in dry dimethylformamide (50 mL). After 15 min stirring, the turbid, orange solution was treated with N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (2.65 g) and the mixture was stirred overnight. The mixture was diluted with 10% hydrochloric acid (125 mL) and extracted with ethyl acetate (2 times 150 mL). The combined extracts were washed with 10% hydrochloric acid and water (twice), dried and evaporated to an orange-brown glass. Purification by flash chromatography (gradient elution, 1%-4% ethyl acetate in dichloromethane) and overnight drying under vacuum yielded the N-alkylated product 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.97 g, 28%); TLC: Rf =0.35, dichloromethane:ethyl acetate (97:3); 300 MHz NMR: 0.08 (s,3), 0.10 (s, 3), 0.81 (d,3, J=6.6), 0.86 (s,9), 0.93 (d,3, J=6.6), 1.67-1.78 (m,1), 3.81 (t,1, J=10), 4.22-4.40 (m,2), 4.64 (broad d,1, J=15), 5.19 (s,2), 6.22 (d,1, J=7.6), 7.33-7.48 (m,10), 7.63 (d,1, J=9.9), 7.92 (d,1, J=7.6), 8.53 (s,1). Also obtained was the O-alkylated product 2-(3-benzyloxycarbonylamino-6-phenylpyrid-2-yloxy)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (2.11 g, 62%); TLC: Rf =0.61, dichloromethane:ethyl acetate (97:3), 300 MHz NMR: 0.01 (s,3), 0.07 (s,3), 0.75 (s,9), 0.77 (d, 3, J=6.6), 0.89 (d,3, J=6.6), 1.67-1.81 (m,1), 3.84 (t,1, J=10), 4.26 (m,1), 4.81 (d,1, J=15), 5.14 (d,1, J=15), 5.20 (s,2), 7.35-7.48 (m,9), 7.62 (d,1, J=8), 7.99 (dd,2, J=1.6, J=8.4), 8.12 (d,1, J=8), 9.31 (s,1); MS: m/z=646(M+1). (A mixed fraction (0.25 g, 7%) was also obtained).
