Reaction #710523

Reaction equation

(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-((1R,2S)-2-hydroxy-1,2-diphenyl-ethyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide

cerium ammonium nitrate

sodium hydrogencarbonate

acetonitrile

→

(2′S,3′R,4′S,5′R)-6-Chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide

Solvents

ethyl acetate

acetone

water

Conditions

Workup

1. 1
   OtherIn a three-neck 50 mL flask were successively introduced
2. 2
   workup.ADDITIONwere added
3. 3
   workup.STIRRINGstirring
4. 4
   Temperaturewas maintained for 5 minutes
5. 5
   Otherdecanted
6. 6
   OtherThe organic phase was separated
7. 7
   Extractionthe aqueous phase was extracted twice with 10 mL of ethyl acetate
8. 8
   WashThe combined organic extracts were washed with 20 mL of water
9. 9
   Dryingdried with magnesium sulfate
10. 10
    Concentrationconcentrated to dryness under reduced pressure
11. 11
    OtherThe residue was purified by flash chromatography on a 30 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane; flow: 30 mL/min)
12. 12
    Otherfollowed by a second purification by flash chromatography on a 15 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol/28% ammonia 97/2/1 v/v/v; flow: 30 mL/min) 87 mg of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide
13. 13
    Otherwere obtained as a white solid

Procedure

In a three-neck 50 mL flask were successively introduced 0.70 g (0.91 mmol) of (2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-1′-((1R,2S)-2-hydroxy-1,2-diphenyl-ethyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide, 7.0 mL of acetonitrile, 3.5 mL of distilled water and 3.5 mL of acetone. The resulting mixture was stirred and cooled to 0° C. and 0.99 g (1.81 mmol) of cerium ammonium nitrate was added in small portions. The reaction mixture was stirred at 0° C. for 20 minutes, upon which 89 mg (1.06 mmol) of sodium hydrogencarbonate were added and stirring was maintained for 5 minutes. The mixture was diluted with 60 mL of ethyl acetate and decanted. The organic phase was separated and the aqueous phase was extracted twice with 10 mL of ethyl acetate. The combined organic extracts were washed with 20 mL of water, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on a 30 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane; flow: 30 mL/min) followed by a second purification by flash chromatography on a 15 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol/28% ammonia 97/2/1 v/v/v; flow: 30 mL/min) 87 mg of (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (trans-4-hydroxy-cyclohexylmethyl)-amide were obtained as a white solid. mp: 192° C. (Kofler); LC-MS: tR (min)=0.84; [M+H]+: m/z 576; [M−H]−: m/z 574 (method A); 1H NMR (CHLOROFORM-d, 400 MHz): mixture of isomers: 0.90 (s, 9H); 0.99 to 2.09 (m partially hidden, 11H); 3.05 to 3.27 (m, 2H); 3.59 (m, 2H); 4.39 (d, J=8.8 Hz, 1H); 4.59 (m, 1H); 6.76 (s large, 1H); 6.99 (t, J=7.8 Hz, 1H); 7.06 to 7.56 (m, 6H); 7.82 (t broad, J=6.1 Hz, 1H).

Source