1-Piperidinecarboxaldehyde → 8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carbonyl chloride

Participants

Reaction Conditions

Reaction Steps

To a 3000 mL three-neck round bottom flask equipped with an overhead stirrer, thermo pocket, addition funnel and nitrogen tube was charged toluene (1000 mL), N-formyl piperidine (3.54 g, 0.031 mol) and thionyl chloride (67 g, 0.559 moles) at 23° C. under nitrogen atmosphere. The resultant reaction mass was heated to 82° C. and to this 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (100 g, 0.373 moles) (prepared as in WO 2010/129500) was charged lot wise (5 lots) over a period of 60 min. The walls of the reactor were rinsed with 500 mL toluene. After addition, the resultant reaction mass was stirred at 90° C. for 75 min and the progress of the reaction was monitored by HPLC. For this, 0.5 mL of the reaction mass was diluted with 3 mL of methanol and the formation of acid chloride was analyzed indirectly by detecting its corresponding methyl ester by HPLC). After 2 hours, HPLC analysis indicated about 0.35 a % of unreacted 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid and about 99.0 a % of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester. The resultant reaction mass was further heated to 140° C. (oil bath temperature) and distilled at about 109° C. (mass temperature) and 105-107° C. (vapor temperature) at atmospheric pressure over a period of 2.5 hours to remove toluene (about 600 mL) and excess thionyl chloride present in the reaction mass. After distillation, the reaction mass was gradually cooled to 30° C. over a period of 60 min. The concentration of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid was about 0.07 a % and the concentration of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid methyl ester about 99.2 a % as measured by HPLC at 230 nm.

Provenance & Evidence