Diisopropylethylamine → HCID 131736481, compound

HRID 1477169Notes

Reaction equation

HRID 1477169 reaction equation
CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:32][C@@H:33]([CH:56]([CH3:58])[CH3:57])[C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][C@H:37]1[C:45]([NH:47][C:48]1[C:53]([F:54])=[CH:52][CH:51]=[CH:50][C:49]=1[F:55])=[O:46])=[O:35].[C:59]([O:63][C:64]([N:66]([CH3:72])[C@@H:67]([CH3:71])[C:68](O)=[O:69])=[O:65])([CH3:62])([CH3:61])[CH3:60].C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[F:55][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]([F:54])[C:48]=1[NH:47][C:45]([C@@H:37]1[CH2:38][C:39]2[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:36]1[C:34](=[O:35])[C@@H:33]([NH:32][C:68](=[O:69])[C@@H:67]([N:66]([CH3:72])[C:64](=[O:65])[O:63][C:59]([CH3:60])([CH3:62])[CH3:61])[CH3:71])[CH:56]([CH3:58])[CH3:57])=[O:46]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 7009590(2S)-2-(((tert-butoxy)carbonyl)(methyl)amino)propanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 118340306HCID 118340306, compound

Product 1

HCID 131736481HCID 131736481, compoundYield 81.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

TFA (2 mL, 26.0 mmol, Eq: 76.8) was added to a solution of tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.16 g, 338 μmol, Eq: 1.00) in DCM (2 mL) and the resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was azeotroped with n-heptane (20 mL) to give a viscous oil (0.16 g) which was used directly without further purification. HATU (0.21 g, 552 μmol, Eq: 1.68) was added to a solution of (S)-1-((S)-2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)indoline-2-carboxamide 2,2,2-trifluoroacetate (0.16 g, 328 μmol, Eq: 1.00), (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (0.1 g, 492 μmol, Eq: 1.5) and diisopropylethylamine (0.29 mL, 1.66 mmol, Eq: 5.06) in DMF (2 mL) and the reaction was stirred at rt for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with 0.1 M aqueous NaOH (10 mL) and 0.1 M aqueous HCl (10 mL). Hexanes (20 mL) were added to the organic layer and it was washed with water (3×10 mL) and brine. The organic layer was concentrated in vacuo and the resulting crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (0.15 g), m/z=559 (M+H).

Workup

  1. customwas used directly without further purification
  2. washwashed with 0.1 M aqueous NaOH (10 mL) and 0.1 M aqueous HCl (10 mL)
  3. additionHexanes (20 mL) were added to the organic layer and it
  4. washwas washed with water (3×10 mL) and brine
  5. concentrationThe organic layer was concentrated in vacuo
  6. customthe resulting crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-b2caeb7c1412454183753a1a5e31f6b8
Source dataset
uspto-grants-2016_08
Patent number
US09403768B2

Reaction notes

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