Triethylamine → rac-(2'S,3'R,4'R,5'R)-6-chloro-4'-(3-chloro-5-fluoro-phenyl)-2'-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid tert-butyl ester

To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (6 g, 28 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one (5 g, 16 mmol) prepared in Example 85 in dichloromethane (200 mL) were added triethyl amine (15 mL, 109 mmol) and AgF (2.7 g, 218 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (33 g, 130 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel 120 g, 10-40% EtOAc in hexanes) to give as rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a light yellow solid (1.5 g, 18%)

1. concentrationThe mixture was concentrated
2. customthe residue was partitioned between ethyl acetate and brine
3. customThe organic layer was separated
4. washwashed with water
5. dry with materialdried over MgSO4
6. concentrationconcentrated
7. additionwas added
8. temperatureThe reaction mixture was heated at 120° C. for 2 h
9. temperatureThe mixture was then cooled to room temperature
10. concentrationconcentrated
11. customThe residue was partitioned between ethyl acetate and water
12. customThe organic layer was separated
13. extractionthe aqueous layer was extracted with ethyl acetate
14. washwashed with water, brine
15. dry with materialdried over MgSO4
16. concentrationconcentrated
17. customThe residue was purified by chromatography (silica gel 120 g, 10-40% EtOAc in hexanes)

ORD-Eintrag

ord-6b2393c601b443f1a3ebf5b69477d8ef

Quelldatensatz

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08088815B2