反应详情

温度

-78 °C

In flame-dried glassware, 1,3-dioxo-2-(2,2,2-trifluoro-ethyl)-hexahydroimidazo[1,5a]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(tnimethylsilyl)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.

1. extractionextracted with CH2Cl2 (3×150 mL)
2. dry with materialdried with MgSO4
3. customevaporated
4. additionadded 50 mL of dry THF with some molecular sieves
5. additionThe resulting solution of 2-picolyl chloride free base was added to the reaction mixture at −78° C. via syringe
6. temperatureto warm to room temperature overnight
7. customThe toluene and THF were evaporated
8. customresulting DMF solution
9. customwas partitioned with 150 mL of H2O/150 mL of IPE
10. stirringthe solution was stirred for one hour
11. customto remove excess 2-picolyl chloride
12. customThe organic solvents were separated
13. customwere removed by evaporation