Hydrochloric Acid → rac-(2'S,3'S,4'S)-6-chloro-2'-(3-chloro-2-fluoro-phenyl)-4'-(4-hydroxy-2,2-dimethyl-butyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-1'-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide

To a solution of rac-(2′S,3′S,4′S)-4′-[4-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-butyl]-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 40 (70 mg, 0.12 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHCO3 solution (5 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.12 mL, 0.22 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated. The residue was dissolved into tetrahydrofuran (5 mL), and 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (36 mg, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 5 mL, 5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. 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 (15% MeOH in EtOAc) to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(4-hydroxy-2,2-dimethyl-butyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 13 mg, 18%).

1. customwas lowered to 0° C.
2. customThe organic layer was separated
3. extractionthe aqueous layer was extracted with dichlormethane twice
4. washThe combined organic layers were washed with water, brine
5. dry with materialdried over MgSO4
6. concentrationconcentrated
7. additionwas added
8. stirringThe reaction mixture was stirred at room temperature for 1 h
9. stirringThe reaction mixture was stirred at room temperature for 1 h
10. customThe solvents were removed
11. customthe residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution
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 (15% MeOH in EtOAc)

ORD record

ord-b1e4775168e741cdb63fbd39083f5f0d

Source dataset

uspto-grants-2012_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08288431B2