反应详情

To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (200 mg) obtained in Example 137a, 1-(hydroxyacetyl)piperidine-4-carboxylic acid (129 mg) and triethylamine (127 μL) in acetonitrile (5 mL) were added WSC.HCl (176 mg) and HOBt (140 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), potassium carbonate (317 mg) was added, and the mixture was stirred at room temperature for 3 hr. The solution was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 15→100% ethyl acetate/hexane) to give 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-{[1-(hydroxyacetyl)piperidin-4-yl]carbonyl}piperidin-4-yl]-N-methylbenzamide (108 mg, 41%) as a white powder.

1. extractionthe resultant product was extracted with ethyl acetate
2. washThe organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine
3. customdried
4. customthe solvent was evaporated under reduced pressure
5. dissolutionThe obtained residue was dissolved in methanol (5 mL)
6. additionpotassium carbonate (317 mg) was added
7. stirringthe mixture was stirred at room temperature for 3 hr
8. concentrationThe solution was concentrated
9. custompartitioned between ethyl acetate and water
10. washThe organic layer was washed with water
11. customdried
12. customthe solvent was evaporated under reduced pressure
13. customThe obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 15→100% ethyl acetate/hexane)