Phosphorus oxychloride → tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

HRID 1477168Notes

Reaction equation

HRID 1477168 reaction equation
P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH2:9].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH:38]([CH3:40])[CH3:39])[C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C@H:27]1[C:35](O)=[O:36])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH:9][C:35]([C@@H:27]1[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:38]([CH3:40])[CH3:39])=[O:36]

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 796472,6-DifluoroanilineHCID 10618657(S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid

Product 1

HCID 131736480tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamateYield 89.2%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

Phosphorus oxychloride (164 mg, 0.1 mL, 1.07 mmol, Eq: 2.16) was added dropwise to a cooled (ice-bath) solution of 2,6-difluoroaniline (264 mg, 0.22 mL, 2.04 mmol, Eq: 4.12) and (S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid (0.18 g, 497 μmol, Eq: 1.00) in pyridine (4 mL). The cooling bath was removed and the reaction was stirred at rt. After 1 h the reaction mixture was diluted with toluene (10 mL) and concentrated in vacuo. The residue was treated with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with 0.1 M aqueous HCl (10 mL) and brine (10 mL) and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.21 g), m/z=474 (M+H).

Workup

  1. customThe cooling bath was removed
  2. additionAfter 1 h the reaction mixture was diluted with toluene (10 mL)
  3. concentrationconcentrated in vacuo
  4. additionThe residue was treated with water (10 mL)
  5. extractionextracted with EtOAc (2×10 mL)
  6. washThe combined organic layers were washed with 0.1 M aqueous HCl (10 mL) and brine (10 mL)
  7. concentrationconcentrated in vacuo
  8. customThe crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% EtOAc in hexanes)

Sources & evidence

ORD record
ord-b3850ff0cbd64994b54de88042e2ffc9
Source dataset
uspto-grants-2016_08
Patent number
US09403768B2

Reaction notes

Loading…