2-Methyl-6-indolizinecarbonitrile synthesis

Yield:22320-36-1 84%

Reaction Conditions:

Stage #1: 6-methylnicotinonitrile;1-bromoacetone in sulfolane at 45; for 48 h;
Stage #2: with sodium hydrogencarbonate in water; for 1 h;Heating / reflux;

Steps:

24

1-Bromo-propan-2-one (2.26 ml) is added under an atmosphere of argon to a solution of 5- cyano-2-methylpyridine (5.0 g, 41.9 mmol) in sulfolane (30 ml). The reaction mixture is stirred for 48 hours at 45 ⁰C, then diluted with EtOAc. The precipitated salt is filtered off and dissolved in water (50 ml). The aqueous solution is washed with EtOAc, then a 10% aqueous solution of NaHCO₃ (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the reaction mixture is filtered, and the filtrate is extracted three times with EtOAc. The combined organic layers are dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue is purified via flash chromatography (hexane / EtOAc 8 : 1 , + 0.2% NEt₃) to afford the title compound (5.50 g, 84%). ¹H NMR (400 MHz, d₆-DMSO): δ = 9.10 - 9.09 (m, 1 H), 7.59 (s, 1 H), 7.55 (d, J = 9.0 Hz, 1 H), 6.90 (dd, J = 9.3 / 1.7 Hz, 1 H), 6.55 (s, 1 H), 2.39 (s, 3H). MS (ES⁺): 157 (M+H)⁺.

References:

WO2008/74752,2008,A2 Location in patent:Page/Page column 20-21