Triethylamine → 3-[4-(4-Methylamino-3-nitro-phenoxy)-pyridin-2-ylcarbamoyloxy]-azetidine-1-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

To a suspension of acid 1 (1 eq.) in dry THF (10 mL) at 0° C. was added triethylamine (3.0 eq.) and the resulting reaction was maintained at 0° C. for 45 min to afford a homogenous solution. Diphenylphosphoryl azide (DPPA, 1.1 eq) was added and the reaction was maintained o/n allowing the cooling bath to expire. The reaction was concentrated and the resulting residue dissolved in CH2Cl2. The organic portion was washed with saturated NaHCO3 (3×) and the combined aqueous phases were extracted with CH2Cl2. The combined organic portions were dried (MgSO4), filtered, and concentrated. The remaining residue was suspended in toluene. To this suspension was added N-BOC azetidin-2-ol (1 eq) and the reaction mixture was heated to and maintained at 100° C. for 1 h. The reaction was then allowed to cool to rt and concentrated. The residue was dissolved in CH2Cl2 and washed with saturated Na2CO3 (3×). The combined aqueous phases were extracted with CH2Cl2 and the combined organic layers were washed with Na2CO3 and brine, dried (MgSO4), and evaporated. The crude residue was adsorbed onto SiO2 and purified by flash chromatography (9:1, 4:1, 2:1, 1:1 hexanes-EtOAc) to furnish 625 mg (70%) of a light orange solid as 2: 1H NMR (300 MHz, CDCl3) δ 9.32 (br, s, 1 H), 8.17 (d, J=6.0 Hz, 1 H), 8.06 (br dd, J=5.0, 10.2 Hz, 1 H), 7.96 (d, J=2.8 Hz, 1 H), 7.52 (d, J=2.5 Hz, 1 H), 7.30 (dd, J=2.8, 9.2 Hz, 1 H), 6.93 (d, J=9.2 Hz, 1 H), 6.57 (dd, J=2.5, 6.0 Hz, 1 H), 5.18 (dddd, J=4.4, 4.4, 6.9, 6.9 Hz, 1 H), 4.25 (ddd, J=0.8, 6.9, 10.1 Hz, 2 H), 3.94 (ddd, J=0.8, 4.4, 10.1 Hz, 2 H), 3.07 (d, J=5.2 Hz, 3 H), 1.43 (br s, 9 H).

Provenance & Evidence