Toluene → HCID 178444602, compound

HRID 623338Notes

Reaction equation

HRID 623338 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:53])[C@:10]3([C@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@@H:13]([C:23]([NH:25][C@H:26]4[CH2:31][CH2:30][C@H:29]([OH:32])[CH2:28][CH2:27]4)=[O:24])[N:12]([C@@H](C4C=CC=CC=4)[C@H](O)C4C=CC=CC=4)[C@H:11]3[CH2:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:5]2=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O.C(OC(C)C)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:53])[C@:10]3([C@H:14]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=4[F:22])[C@@H:13]([C:23]([NH:25][C@H:26]4[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]4)=[O:24])[NH:12][C@H:11]3[CH2:48][C:49]([CH3:51])([CH3:50])[CH3:52])[C:5]2=[CH:4][CH:3]=1

Participants

7

Reactant 3

HCID 1140TolueneHCID 8857Ethyl AcetateHCID 178444591HCID 178444591, compound

Product 1

HCID 178444602HCID 178444602, compoundYield 39.3%

Reagents, catalysts & solvents 3

HCID 702EthanolSolvent2×HCID 7914Diisopropyl EtherSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 542 mg (0.71 mmol) of (2′S,3R,4′R,5′S)-6-chloro-4′-(3-chloro-2-fluorophenyl)-1′-((1S,2R)-2-hydroxy-1,2-diphenylethyl)-N-((trans)-4-hydroxycyclohexyl)-2′-neopentyl-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide in 10 mL of ethanol was cooled to 0° C. and 989 mg (1.79 mmol) of ceric ammonium nitrate was added slowly via spatula in 15 min. The reaction mixture was stirred at 0° C. for 1 hour, upon which it was treated with 4 mL of toluene, 2 mL of ethanol, 5 mL of saturated brine and 3 mL of ethyl acetate, and decanted. The organic phase was separated and the aqueous phase was extracted with 2×5 mL of ethyl acetate. The organic phases were combined and washed with 3 mL of 5% sodium carbonate. After decantation, the aqueous phase was diluted with water and reextracted with 10 mL of ethyl acetate. The organic phases were combined and successively washed with 2 mL of 11% sodium disulfite and 2 mL of saturated brine. It was then dried over magnesium sulfate and concentrated to dryness under reduced pressure. 222 mg of the residue was purified by flash chromatography on a 40 g silica cartridge (15 μm silica gel; eluting solvent: dichloromethane/acetone 75/25 v/v followed by 65/35 v/v; flow: 30 mL/min) 0.183 g of an off-white meringue was obtained, taken up twice in diisopropyl oxide and dried at 25° C. under reduced pressure. 157 mg of (2′S,3R,4′R,5′S)-6-chloro-4′-(3-chloro-2-fluorophenyl)-N-((trans)-4-hydroxy-cyclohexyl)-2′-neopentyl-2-oxospiro[indoline-3,3′-pyrrolidine]-5′-carboxamide were obtained as a white amorphous solid. mp: 176° C. (Kofler); LC-MS: tR (min)=1.13 (91%) and 1.03 (9%); [M+H]+: m/z 562; [M−H]−: m/z 560 (method C); 1H NMR (400 MHz, DMSO-d6): 0.76 (s, 9H); 0.85 (dd, J=1.8 and 14.3 Hz, 1

Workup

  1. customdecanted
  2. customThe organic phase was separated
  3. extractionthe aqueous phase was extracted with 2×5 mL of ethyl acetate
  4. washwashed with 3 mL of 5% sodium carbonate
  5. additionAfter decantation, the aqueous phase was diluted with water
  6. washsuccessively washed with 2 mL of 11% sodium disulfite and 2 mL of saturated brine
  7. dry with materialIt was then dried over magnesium sulfate
  8. concentrationconcentrated to dryness under reduced pressure
  9. custom222 mg of the residue was purified by flash chromatography on a 40 g silica cartridge (15 μm silica gel; eluting solvent: dichloromethane/acetone 75/25 v/v followed by 65/35 v/v; flow: 30 mL/min) 0.183 g of an off-white meringue
  10. customwas obtained
  11. customdried at 25° C. under reduced pressure

Sources & evidence

ORD record
ord-47b5a224b05c4b699af54a6a4382ab72
Source dataset
uspto-grants-2016_04
Patent number
US09302120B2

Reaction notes

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