2-Methoxyaniline → [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine

Participants

Reaction Conditions

Reaction Steps

In a dry tube under an atmosphere of argon to a solution of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(4R,5R)-4-(5-bromo-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.3) (150 mg, 247 μmol) in dioxane (5 ml) was added consecutively sodium tert-butoxide (26.1 mg, 272 μmol), 2-di-tert-butylphosphino-2′4′,6′-triisopropylbiphenyl (10.5 mg, 24.7 μmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (7.9 mg, 7.41 μmol), and 2-methoxyaniline (60.8 mg, 55.7 μl, 494 μmol). The tube was sealed and heated 115° C. under stirring during 15 hours. For the workup, the reaction mixture was evaporated at reduced pressure, and the residue was purified by chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 60:30 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(4R,5R)-5-fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl}-amine (51 mg, 32% yield) was obtained as a pale yellow foam. MS (ISP): m/z=650.5 [M+H]+.

Provenance & Evidence