Pivalic acid → 5-(2,2-dimethylpropanoyl)-N-hydroxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide

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Reaction Steps

To a solution of HATU (104 mg, 0.274 mmol) and trimethylacetic acid (28 mg, 0.274 mmol) in DCM (2 mL) was added triethylamine (104 μL, 0.203 mmol). The reaction solution was stirred at room temperature for 30 min. A solution of ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (20 mg, 0.101 mmol; prepared as described in J. Med. Chem. 2006, 49(15):4623-4637) in DMF (0.5 mL) was added in one portion. The solution was then stirred at room temperature overnight. The solution was then diluted with DCM and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM twice, the combined organic phases were additionally washed with water, brine, dried over anhydrous MgSO4 and concentrated to afford an oil residue. To the material thus obtained was added methanol (2 mL), hydroxylamine hydrochloride (52.1 mg, 0.75 mmol), and potassium hydroxide (84.2 mg, 1.5 mmol). The reaction mixture was heated at 80° C. for 3 h, cooled to room temperature and the solvent removed in vacuo. The solid residue obtained was dissolved in DMSO (1.4 mL) and purified with Gilson prep-HPLC [282 nm, rt=5.2 (12 min), 15-40% MeCN—H2O] to afforded white solid (16.1 mg, 24%) as a white solid. LCMS: (FA) ES+ 283; 1H NMR (d6,DMSO, 400 MHz) δ 11.13 (s, 1 H), 9.08 (s, 1 H), 7.37 (s, 1 H), 4.56 (s, 2 H), 3.83 (t, J=5.8 Hz, 2 H), 2.83 (t, J=5.4 Hz, 2 H), 1.22 (s, 9 H).

Provenance & Evidence