tert-Butanol → 4-Benzyl-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepane

To a mixture of 4-(4-benzyl-[1,4]oxazepan-6-yl)-benzonitrile (1.0 g, 3.4 mmol) in tert-butyl alcohol (10 mL) at room temperature was added finely powdered potassium hydroxide (2.0 g, 30 mmol) and the resulting mixture was refluxed for 3 hours with vigorous stirring. After cooling to room temperature, the reaction mixture was diluted with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was dissolved in dimethylformamide dimethylacetal (3 mL) at room temperature. The solution was heated to 110° C. and stirred for one hour. After removal of excess dimethylformamide dimethylacetal under reduced pressure, the residual oil was dissolved in 1,4-dioxane (3 mL). To the resulting mixture at room temperature was added hydroxylamine hydrochloride (0.09 g, 1.3 mmol), acetic acid (3 mL) and 1M aqueous solution of sodium hydroxide (1.5 mL) and the mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated. Purification of the residue by flash column chromatography on silica gel (hexane/ethyl acetate=80/20 to 50/50 as an eluant) was performed to yield 4-benzyl-6-(4-[1,2,4]oxadiazol-5-yl-phenyl)-[1,4]oxazepane as colorless oil (0.03 g, 0.11 mmol, 8%).

1. temperaturethe resulting mixture was refluxed for 3 hours with vigorous stirring
2. extractionextracted with chloroform
3. dry with materialThe organic layer was dried over anhydrous sodium sulfate
4. concentrationconcentrated
5. dissolutionThe resulting residue was dissolved in dimethylformamide dimethylacetal (3 mL) at room temperature
6. temperatureThe solution was heated to 110° C.
7. customAfter removal of excess dimethylformamide dimethylacetal under reduced pressure
8. dissolutionthe residual oil was dissolved in 1,4-dioxane (3 mL)
9. temperaturethe mixture was refluxed for 2 hours
10. temperatureAfter cooling to room temperature
11. extractionextracted with ethyl acetate
12. dry with materialThe organic extracts were dried over anhydrous sodium sulfate
13. concentrationconcentrated
14. customPurification of the residue by flash column chromatography on silica gel (hexane/ethyl acetate=80/20 to 50/50 as an eluant)

ORD record

ord-2845cf8bfec245beba23bd2871894e31

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09108957B2