Anisole → (R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one

Participants

Reaction Conditions

Reaction Steps

A solution of (R)-3-(5-bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-3-methyl-[1,4]oxazepan-5-one (2.278 g, 5.39 mmol) and anisole (10.7 g, 98.7 mmol) in trifluoroacetic acid (28 ml) was treated dropwise within 6 minutes at room temperature with trifluoromethanesulfonic acid (9.47, 61.9 mmol). After complete addition, the reaction mixture was heated at 73° C. for 24 hours. Following TLC no starting material in a complex mixture of products. For the workup, the cold mixture was poured carefully under stirring into a mixture of saturated sodium hydrogen carbonate solution (200 ml) and ice. The extraction with ethyl acetate (500 ml) and re-extraction of the separated aqueous layer with ethyl acetate (250 ml) was followed by washing the combined organic layers with saturated sodium hydrogen carbonate solution (200 ml) and brine (200 ml). The organic phase was dried over sodium sulfate, then evaporated at reduced pressure. Chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielded a product containing fraction of 628 mg which was engaged in the next step without further purification and characterisation. For characterisation of the title compound another fraction of 104 mg was again purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielding the pure (R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one (intermediate C11A) as a beige foam (56 mg). MS (ISP): m/z=302.2, 304.1 [M+H]+.

Provenance & Evidence