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

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).

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)

ORDレコード

ord-b3850ff0cbd64994b54de88042e2ffc9

出典データセット

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09403768B2