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

温度

73 °C

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]+.

1. additionAfter complete addition
2. additionFollowing TLC no starting material in a complex mixture of products
3. additionFor the workup, the cold mixture was poured carefully
4. extractionThe extraction
5. extractionwith ethyl acetate (500 ml) and re-extraction of the separated aqueous layer with ethyl acetate (250 ml)
6. washby washing the combined organic layers with saturated sodium hydrogen carbonate solution (200 ml) and brine (200 ml)
7. dry with materialThe organic phase was dried over sodium sulfate
8. customevaporated at reduced pressure
9. customChromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielded a product
10. additioncontaining fraction of 628 mg which
11. customwas engaged in the next step without further purification and characterisation
12. customFor characterisation of the title compound another fraction of 104 mg was again purified by chromatography on Silicycle-Si-amine column

ORDレコード

ord-e6f77e952eeb4b84bc398e40ca4589a5

出典データセット

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08673894B2