Hydrochloric Acid → 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one

Temperature

75 °C

A mixture of 1-(4-bromo-phenyl)-3-chloro-propan-1-ol (25 g, 100 mmol), (R)-1-phenylethylamine (25 mL, 200 mmol), potassium iodide (33 g, 200 mmol) and potassium carbonate (27.6 g, 200 mmol) in acetonitrile (600 mL) was prepared at room temperature and warmed to 75° C. After stirring for 40 hours, solvent was evaporated. And then distillable removal of excess (R)-1-phenylethylamine was performed at 120° C. under reduced pressure. The obtained residue was dissolved in dichloromethane (200 mL) and to the resulting solution was added triethylamine (16.7 mL, 120 mmol) and chloroacetylchloride (10 mL, 120 mmol) at 0° C. After stirring for one hour, the reaction solution was poured into 1N hydrochloric acid aqueous solution and extracted with chloroform. The extracts were dried over anhydrous sodium sulfate and concentrated. The resulting residue was diluted with 2-propanol (100 mL) and to the mixture was added potassium hydroxide (9.9 g, 150 mmol) at room temperature. After stirring for 5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium hydroxide and concentrated. Purification of the residue and separation of each diastereomer were performed by flash column chromatography on silica gel (hexane/ethyl acetate=2/1 to 1/1 as eluants) to yield 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer A; 13.1 g, 35 mmol, 35% in 3 steps) as brown oil and 7-(4-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer B; 11.0 g, 29.4 mmol, 29% in 3 steps) as white solid. 7-(4-Bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer A):

1. customwas prepared at room temperature
2. customsolvent was evaporated
3. customAnd then distillable removal of excess (R)-1-phenylethylamine
4. customwas performed at 120° C. under reduced pressure
5. dissolutionThe obtained residue was dissolved in dichloromethane (200 mL) and to the resulting solution
6. stirringAfter stirring for one hour
7. extractionextracted with chloroform
8. dry with materialThe extracts were dried over anhydrous sodium sulfate
9. concentrationconcentrated
10. additionThe resulting residue was diluted with 2-propanol (100 mL) and to the mixture
11. stirringAfter stirring for 5 hours
12. extractionextracted with ethyl acetate
13. dry with materialThe organic phase was dried over anhydrous sodium hydroxide
14. concentrationconcentrated
15. customPurification of the residue and separation of each diastereomer

ORD record

ord-d847b5ab1bf04f338d5fba3a46d89ae0

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09108957B2