Sodium Bicarbonate → (R)-1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-2-carboxylic acid 4-propyl-benzylamide

To a solution of the compound (6.65 g) obtained in Example 783, Step 2,4-propylbenzylamine (3.26 g) and 1-hydroxybenzotriazole hydrate (2.69 g) in N,N-dimethylformamide (33 ml) was added, with stirring under ice-cooling, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.37 g). After stirring overnight at room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added under ice-cooling, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a crude product (7.40 g). This was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give a crude product containing (R)-3-(4-propyl-benzylcarbamoyl)-4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester as a main component. The obtained crude product was dissolved in 1,4-dioxane (40 ml), 4N hydrogen chloride/1,4-dioxane solution (50 ml) was added at room temperature, and the mixture was stirred at room temperature for 2 hr. Further, 4N hydrogen chloride/1,4-dioxane solution (20 ml) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium carbonate, filtrated, and concentrated under reduced pressure to give a crude product (3.70 g) containing the title compound as a main component. The residue was crystallized from a mixed solvent of diisopropyl ether and n-hexane, and collected by filtration. The obtained crude crystals were suspended in diisopropyl ether, collected by filtration and dried to give the title compound (3.0 g).

1. temperaturecooling
2. stirringAfter stirring overnight at room temperature
3. temperaturecooling
4. stirringthe mixture was stirred at room temperature
5. filtrationThe precipitated solid was collected by filtration
6. washwashed with water
7. customdried under reduced pressure
8. customto give a crude product (7.40 g)
9. customThis was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2)
10. customto give a crude product
11. customThe obtained crude product
12. stirringthe mixture was stirred at room temperature for 2 hr
13. stirringthe mixture was stirred at room temperature for 1 hr
14. concentrationThe reaction mixture was concentrated under reduced pressure
15. customthe residue was partitioned
16. additionby adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate
17. washThe organic layer was washed with saturated brine
18. dry with materialdried over anhydrous sodium carbonate
19. filtrationfiltrated
20. concentrationconcentrated under reduced pressure
21. customto give a crude product (3.70 g)

ORD record

ord-01a0c08a2ab7454e865a5675a3169418

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08017612B2