反应详情

Chloroacetylchloride (1.81 ml, 1.2 eq) was added dropwise to a solution of (RS)-2-amino-2-(3-bromo-phenyl)-2-(4-difluoromethoxy-3-methyl-phenyl)-ethanol (intermediate VIII-4) (4.81 g, 1 eq) and triethylamine (2.78 ml, 1.5 eq) in acetonitrile (70 ml) at −2° C. After complete addition, the solution was left to warm to room temperature and stirring was continued for 5 hours. The reaction mixture was concentrated, washed with brine (3×20 ml), dried over sodium sulphate and concentrated in vacuo. The crude was dissolved in tert-butanol (50 ml), then treated in one portion with potassium tert-butanolate (4.9 g, 3.3 eq) and stirred at 35° C. overnight. The reaction mixture was then treated with water (50 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a 9:1-mixture of cyclohexane and ethyl acetate as the eluent. The (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-morpholin-3-one was obtained as a white solid (4.5 g, 81% of theory). MS (ISP): m/z=413.8 [M+H]+.

1. additionAfter complete addition
2. waitthe solution was left
3. concentrationThe reaction mixture was concentrated
4. washwashed with brine (3×20 ml)
5. dry with materialdried over sodium sulphate
6. concentrationconcentrated in vacuo
7. dissolutionThe crude was dissolved in tert-butanol (50 ml)
8. stirringstirred at 35° C. overnight
9. extractionextracted with ethyl acetate (3×20 ml)
10. customThe combined organic layers were collected
11. dry with materialdried over sodium sulphate
12. concentrationconcentrated in vacuo
13. customThe residue was purified by chromatography on silica gel using a 9