Acetic Acid → Fluazaindolizine

Participants

Reaction Conditions

Reaction Steps

To a stirred slurry of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester (see PCT Patent Publication WO 2010/129500 for preparation) (3 g, 10.3 mmol) and 2-chloro-5-methoxybenzenesulfonamide (see PCT Patent Publication WO 2010/129500 for preparation) (2.4 g, 10.8 mmol, 1.05 equiv) in dichloromethane (24 mL) at 17° C. under nitrogen was added diethyl aluminum chloride (1.5 mL, 12.0 mmol, 1.16 equiv) over approximately 1 minute. The addition of diethylaluminum chloride was accompanied by ca. 13° C. temperature rise and gas evolution. After complete addition of diethylaluminum chloride the temperature of the reaction mixture was adjusted to 40° C. and the batch became an off-white slurry. The reaction mixture was held stirring for about 24 h at 40° C. HPLC analysis (after 24 h) indicated 3.6 area % of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester remaining. Iso-propyl alcohol (1.6 mL) and heptane (12 mL) were respectively added to the reaction resulting in formation of a thicker slurry. Aqueous 10% acetic acid (15 mL, 25.6 mmol, 2.5 equiv) was then added resulting in a strong exotherm. The reaction mass was held for about 1.5 h at 20-25° C. and was then filtered and the filter cake was washed with water (12 ml). The solid product was split into two portions, the larger portion was dried in a vacuum oven at 80° C. for 16 hours and the smaller portion was air-dried for 16 hours to give the title compound (2.8 g and 0.95 g respectively) in 86.8% combined yield. The vacuum-dried product conformed with polymorph Form A and the air-dried portion did not. The polymorph Form A was characterized by its powder X-ray diffraction pattern (See Characterization Example 2).

Provenance & Evidence