1,4-Dioxane → 1-{5-tert-Butyl-2-[3-(2-hydroxy-ethoxy)-4-triisopropylsilanyloxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

Participants

Reaction Conditions

Reaction Steps

A solution of Intermediate 55e (710 mg, 2.17 mmol), Intermediate C (385 mg, 2.17 mmol) and DIPEA (250 μL, 3.25 mmol) in 1,4-dioxane (10 mL) was stirred at 60° C. overnight. After cooling, the mixture was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give a gum (1.25 g, quantitative) that was used without further purification in the next step. TLC [DCM/MeOH (9:1) Rf=0.4]. A solution of the above product (1.25 g, 1.30 mmol) in MeOH (30 mL) was treated with pyridinium p-toluenesulfonate (978 mg, 3.90 mmol) and the resulting mixture was heated at 45° C. overnight. The volatiles were removed under reduced pressure and the residue was taken up in DCM (80 mL) and washed with water (20 mL). The organic phase was separated using a phase separating cartridge and the organic layer was evaporated in vacuo. The product was purified by FCC, eluting with 0-10% MeOH in DCM, to give the title compound (430 mg, 40%). LCMS (Method 3): Rt 5.41 min, m/z 879,880 [MH+].

Provenance & Evidence