反应详情

Potassium hydride (35% dispersion in oil, 110 mg) was added to a solution of 5,11-dihydrodibenzo[b,e][1,4]thiazepine (see Example 1) (570 mg) in DME (8 ml) and the mixture stirred at room temperature for 30 minutes, treated with a solution of (S)-2-(2-chloroethyl)-1-(4-methoxyphenethyl)pyrrolidine (480 mg) (prepared from the corresponding hydrochloride salt prepared in Preparation 4 by stirring a solution of the salt in dichloromethane with a slight excess of 10% aqueous sodium carbonate solution, separating the layers, drying the organic layer over sodium sulphate, and evaporating under reduced pressure to provide the desired free base) in DME (4 ml) and heated under reflux for two hours. The mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, performing a gradient elution using initially dichloromethane/hexane (3:1) as eluant, changing to dichloromethane/methanol (97:3). The appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil, (460 mg, 58%).

1. customprepared in Preparation 4
2. customseparating the layers
3. dry with materialdrying the organic layer over sodium sulphate
4. customevaporating under reduced pressure
5. customto provide the desired free base) in DME (4 ml)
6. temperatureheated
7. temperatureunder reflux for two hours
8. temperatureThe mixture was cooled to room temperature
9. customquenched with water
10. extractionextracted with ethyl acetate
11. washThe organic layer was washed with water
12. dry with materialdried over sodium sulphate
13. customevaporated under reduced pressure
14. customThe residue was purified by chromatography on silica gel
15. washa gradient elution
16. customevaporated under reduced pressure