Reaction #710521

Reaction equation

water

ethyl acetate

(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-cyclohexyl)-amide

acetyl chloride

pyridine

→

Acetic acid 4-{[(2′S,3′R,4′S,5′R)-1,1′-diacetyl-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-cyclohexyl ester

Conditions

Workup

1. 1
   OtherThe organic phase was separated
2. 2
   Extractionthe aqueous phase was extracted twice with ethyl acetate
3. 3
   WashThe combined organic extracts were washed with brine
4. 4
   Dryingdried with magnesium sulfate
5. 5
   Concentrationconcentrated to dryness under reduced pressure
6. 6
   OtherThe residue was purified by flash chromatography on a 50 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol 98/2 v/v; flow: 40 mL/min)
7. 7
   Otherfollowed by a second purification by flash chromatography on a 30 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol 98/2 v/v; flow: 20 mL/min) 123 mg of acetic acid 4-{[(2′S,3R,4′S,5′R)-1,1′-diacetyl-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro [indole-3,3′-pyrrolidin]e-5′-carbonyl]-amino}-cyclohexyl ester
8. 8
   Otherwere obtained as a white powder

Procedure

To a solution of 281 mg (0.50 mmol) 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-cyclohexyl)-amide in 5.0 mL of pyridine under argon, was added 178 μL (2.50 mmol) of acetyl chloride. The resulting mixture was stirred at room temperature for 4 days, upon which it was poured into a mixture of water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulfate and then concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on a 50 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol 98/2 v/v; flow: 40 mL/min) followed by a second purification by flash chromatography on a 30 g silica cartridge (15-40 μm silica gel; eluting solvent: dichloromethane/methanol 98/2 v/v; flow: 20 mL/min) 123 mg of acetic acid 4-{[(2′S,3R,4′S,5′R)-1,1′-diacetyl-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro [indole-3,3′-pyrrolidin]e-5′-carbonyl]-amino}-cyclohexyl ester were obtained as a white powder. LC-MS: tR (min)=1.19; [M+H]+: m/z 688; [M−H]−: m/z 686 (method A).

Source