5-Ethoxy-2-pyridinecarboxylic acid

(80mg, 0.479 mmol) was slurried in N, N-Dimethylformamide (dry) (2 ml), DIPEA (0.100 ml, 0.574 mmol) was added followed by HATU (200 mg, 0.526 mmol). After 15 mins 2-chloroaniline (0.056 ml, 0.526 mmol) was added to the brown suspension and the resulting reaction mixture stirred at room temperature for 20 hours. The reaction mixture was evaporated to dryness. This mixture was added to a cold water/ sat. sodium bicarbonate mixture (2:1, 20 ml) and DCM 20 mL. The product was extracted and the layers were separated over a phase separator. The filtrate was evaporated to dryness to give the product as a brown oil which solidified on standing. The product was purified further by reveleris 12 gram column using heptane-EtOAc gradient (0 to 25%) to afford a white solid. Used as such.5-Ethoxypicolinic acid (53.6 mg, 320 muiotaetaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 51.9 mu, 16 muiotaetaomicron) were added. The mixture was stirred for 2.5 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 5-ethoxypicolinoyl chloride as purple oil (59 mg, quant.). After that, tert-butyl ((3aS, 4R, 8R)-4-(5-amino-2-fluorophenyl)-4, 7, 7-trimethyl-8-oxido-3, 3a, 4, 7-tetrahydro-2H- isothiazolo[l, 5-a][l, 4]thiazin-6-yl)carbamate (Int-16ABp, 80 mg, 188 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N, N-diisopropylethylamine (36.5 mg, 49.4 mu, 283 muiotaetaomicron) was added, followed by a solution of 5-ethoxypicolinoyl chloride (vide supra, 47.5 mg, 256 muiotaetaomicron) in dichloromethane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 24 g, eluting with 2 M ammonia in methanol / dichloromethane, gradient 1:99 to 3:97) to yield, after drying in vacuo (40C, 5 mbar), the title compound as a colorless viscous oil (95 mg, 88% yield). HPLC (method LCMS_fglm) tR = 1.36 min. MS (ES+) m/z 574.4 [M+H].To a solution of To a solution of methyl 5-ethoxypicolinate (0.09 g, 0.497 mmol) in THF (1 mL) and MeOH (1 mL) was added lithium hydroxide solution (1.49 mL, 2.98 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with 1 N HC1solution and ethyl acetate. The organic layer was separated and dried over MgSO4. The filtrate was concentrated in vacuo to give Intermediate 163B (white solid, 0.06 g, 0.359 mmol, 72.3% yield). LC-MS Anal. Calc'd for C8H9N03 167.06, found [M+H] 168.1, T = 0.49 mm (Method A). 'H NMR (400MHz, DMSO-d6) oe: 12.75 (br. s., 1H), 8.35 (d, J=2.6 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.48 (dd, J=8.8, 2.9 Hz, 1H), 4.19 (q, J=6.9 Hz, 2H), 1.37 (t, J=6.9 Hz, 3H)

Molecular Weight:167.16
XLogP3:1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:167.058243149
Monoisotopic Mass:167.058243149
Topological Polar Surface Area:59.4
Heavy Atom Count:12
Complexity:160
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes