Ethanol → 6-Chloro-2-ethoxy-nicotinamide

Participants

Reaction Conditions

Reaction Steps

Refer to synthesis of D46 for preparation of 2,6-dichloro-nicotinamide (1). Freshly prepared sodium ethoxide solution in ethanol (12.1 mL of 2.17 M, 26.2 mmol) was slowly added over 10 min to a solution of 1 (5.01 g, 26.2 mmol) in dimethylformamide (30 mL) at 15° C. [Note: a water bath was used to maintain reaction temperature around 14-16° C.; sodium ethoxide was prepared from reaction of Na solid (1.50 g, 65.2 mmol) with anhydrous EtOH (30.0 mL)]. Upon completion of sodium ethoxide addition, the reaction was stirred for 40 min at 14-16° C. [Note: An aliquot (0.3 mL) of reaction was concentrated. A 1H NMR of aliquot recorded in d6-DMSO showed ˜98% conversion to desired 2]. The reaction was poured into water (500 mL) and extracted with EtOAc (3×400 mL). All organics were combined, dried over Na2SO4, filtered and concentrated to give the title compound as a light gray solid (5.20 g, 95% purity as established by 1H NMR). The title compound was carried forward without further purification. 1H NMR 400 MHz (d6-DMSO) δ8.16 (d, J=8.2 Hz, 1H), 7.76 (br s, 1H), 7.57 (br s, 1H), 7.17 (d, J=7.8 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).

Provenance & Evidence