6-Chloro-3-isopropyl-[1,2,4]triazolo[4,3-a]pyrazine → 6-(2,4-Difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)imidazo[2,1-b]oxazole

Participants

Reaction Conditions

Reaction Steps

A 25 mL 3 necked round bottom flask with stir bar, nitrogen line, thermometer and septum was charged with 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]oxazole (0.458 g, 1.322 mmol, Preparation #C.1) and THF (6 mL). The solution was cooled to about −35° C. then i-PrMgCl (2.0 M in THF, 0.730 mL, 1.45 mmol) was added dropwise. After about 10 min zinc chloride (0.225 g, 1.653 mmol) in THF (2 mL) was added while maintaining the temperature of the mixture at about −30° C. The suspension was stirred at about −25 to −30° C. for about 15 min then a solution of 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-a]pyrazine (0.260 g, 1.32 mmol) and Pd(Ph3P)4 (0.076 g, 0.066 mmol) in DMF (2 mL) was added. The mixture was immediately heated in an oil bath preheated to about 85° C. for about 45 min. The reaction mixture was cooled to ambient temperature, concentrated under reduced pressure then dissolved in HOAc (approx. 0.5 mL) and DMF (such that volume was about 9 mL). The material was purified in three equal portions by RP-HPLC (Table 1, method p). The fractions containing product were combined then most of the ACN was removed under reduced pressure. The solution was basified with 2 N aqueous NaOH then extracted with DCM (25 mL then 10 mL). The organic solutions were combined and dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel using DCM/MeOH (95:5) as an eluent. The fractions with product were combined then concentrated under reduced pressure. The light yellow solid was dissolved in hot ACN (about 1 mL) then added dropwise to rapidly stirring water (10 mL). The solid was collected by filtration then dried under vacuum at about 80° C. to give the title compound (0.009 g, 2%): LC/MS (Table 1, Method g) Rt=1.83 min; MS m/z: 381.1 (M+H)+.

Provenance & Evidence