Hydrochloric Acid → 1,3-Dioxo-8a-pridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydroimidazo [1,5-a]pyrazine-7-carboxylic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

In flame-dried glassware, 1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (prepared as described in Step 4, 10.11 g, 30 mmol) was dissolved in 150 mL of DMF/30 mL of THF and cooled to −78° C. Potassium bis(trimethylsilyl)amide (KHMDS, 0.5 M solution, 90 mL, 45 mmol) was added dropwise and allowed to stir for 1 h at −78° C. In separate glassware, 2-picolyl chloride.HCl (14.76 g, 90 mmol) was reacted with saturated aqueous NaHCO3 (150 mL), extracted with CH2Cl2 (3×150 mL), dried with MgSO4, evaporated and added 50 mL of dry THF with some molecular sieves. The resulting solution of 2-picolyl chloride free base was added to the reaction mixture at −78° C. via syringe and allowed to warm to room temperature overnight. The toluene and THF were evaporated and resulting DMF solution was partitioned with 150 mL of H2O/150 mL of IPE. 1,4-Diazabicyclo[2,2,2]octane (7.3 g, 65 mmol) and K2CO3 (12 g, 90 mmol) were added to the solution and the solution was stirred for one hour to remove excess 2-picolyl chloride. The organic solvents were separated and were removed by evaporation to give 11.45 g (89%) of essentially pure title compound.

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