반응 #710523

반응 방정식

(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

용매

ethyl acetate

acetone

water

반응 조건

후처리

1. 1
   기타In a three-neck 50 mL flask were successively introduced
2. 2
   workup.ADDITIONwere added
3. 3
   workup.STIRRINGstirring
4. 4
   온도was maintained for 5 minutes
5. 5
   기타decanted
6. 6
   기타The organic phase was separated
7. 7
   추출the aqueous phase was extracted twice with 10 mL of ethyl acetate
8. 8
   세척The combined organic extracts were washed with 20 mL of water
9. 9
   건조dried with magnesium sulfate
10. 10
    농축concentrated to dryness under reduced pressure
11. 11
    기타The 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
    기타followed 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
    기타were obtained as a white solid

실험 절차

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).

출처