3-tert-butoxycarbonylamino-pyridine-2-carboxylic Acid Methyl Ester

The discussion and purpose for the synthesis of the 2, 3-pyridinecarboxylicacid-2-methylester 1 has been reported elsewhere [1]. To a solution of half-ester (1.0 g, 5.52 mmol) in dry tetrahydrofuran (15 ml) cooled at –10°C was added drop-wise triethylamine (1.52 ml, 11.04 mmol) then ethyl chloroformate (0.79 ml, 8.28 mmol). The mixture was stirred for 30 minutes at –10°C. Analysis by tlc showed complete conversion to a very non-polar product. A solution of sodium azide (0.61 g, 9.38 mmol) in water (4 ml) was then added drop wise continued stirring for 1h at –10°C. The resulting mixture was filtered, evaporated and the aqueous phase was extracted with ethyl acetate (3 x 15 ml). The combined organic layer were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo. The acyle azide was slowly brought to reflux in toluene for 2h to give by Curtius rearrangement cleanly isocyanate. The subsequent reaction of isocyanate with 2-Methyl-2-propanol at 100°C for 3 hours. After evaporation in vacuo, the crude product was purified by chromatography on silica gel (9/1 : EtOAc/petroleum ether) to give 3-tert-Butoxycarbonylamino-pyridine-2-carboxylic acid methyl ester 2 (1.03 g, 80%).

R_f: 0.36 (9:1, EtOAc/petroleum ether)

Melting point: 94°C (pale white crystals, from hexane)

IR (KBr,υ, cm^-1): 3298, 3000 (NH), 1721, 1691 (CO).

¹H-NMR (300 MHz, DMSO-d₆, δ, ppm): 1.47 (s, 9H, CH₃), 3.85 (s, 3H, CH₃), 7.55 ( dd, 1H, J = 8.5, 4.3 Hz, H-5), 8.32 (dd, 1H, J = 4.3, 1.3 Hz, H-4), 8.41 (dd, 1H, J = 8.5, 1.3, H-6), 9.90 (s, 1H, NH).

¹³C- NMR (75 MHz, DMSO-d₆, δ, ppm): 27.82 (3CH₃), 52.44 (CH₃O), 80.62 (C(CH₃)₃), 127.54, 127.71, 134.25, 137.28, 142.25, 152.17, 167.00 (CO).

MS m/z: 253 [M+1], 197.5, 165.0, 153.0, 139.0, 121.5.

Elemental analysis: Calculated C₁₂H₁₆ N₂O₄: C, 57.13; H, 6.39; N, 11.10 Found: C, 57.21; H, 6.45; N, 11.07.