Formaldehyde → Tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(tri methylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A mixture of 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (Example #100, Step A, 0.250 g, 0.417 mmol) and paraformaldehyde (neat, 0.250 g, 8.34 mmol) in iPrOH (5 mL) and AcOH (0.5 ml) was stirred at 110° C. for 2 days. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. Then, MeOH (5 mL), AcOH (2.5 mL) and NaBH3CN (0.524 g, 8.34 mmol) were added. The mixture was stirred at 60° C. for 1 h. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give tert-butyl 3-methyl-3-(methyl(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (0.135 g, 53%). 1H NMR (CDCl3, 400 MHz): δ 7.25 (s, 1H), 6.72 (s, 1H), 5.10 (m, 2H), 4.65 (m, 1H), 4.66 (q, J=13.2 Hz, 2H), 4.03 (d, J=8.8 Hz, 1H), 3.90 (d, J=12.4 Hz, 1H), 3.66 (t, 2H), 3.58 (t, 2H), 2.68 (s, 3H), 1.48 (s, 3H), 1.47 (d, J=6.4 Hz, 3H), 1.42 (s, 9H), 0.99 (m, 2H), 0.00 (s, 9H).

Provenance & Evidence