Diisopropylethylamine → tert-butyl (1R)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamate

HRID 627052Notes

Reaction equation

HRID 627052 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[NH:51][C:52]([CH:54]1[NH:62][C:57]2=[N:58][CH:59]=[CH:60][CH:61]=[C:56]2[CH2:55]1)=[O:53]>C(Cl)Cl.CCOC(C)=O>[F:50][C:46]1[CH:47]=[CH:48][CH:49]=[C:44]([F:43])[C:45]=1[NH:51][C:52]([CH:54]1[N:62]([C:10](=[O:12])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:57]2=[N:58][CH:59]=[CH:60][CH:61]=[C:56]2[CH2:55]1)=[O:53].[F:50][C:46]1[CH:47]=[CH:48][CH:49]=[C:44]([F:43])[C:45]=1[NH:51][C:52]([CH:54]1[N:62]([C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:57]2=[N:58][CH:59]=[CH:60][CH:61]=[C:56]2[CH2:55]1)=[O:53]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2774761Tetramethylfluoroformamidinium hexafluorophosphateHCID 25260122(S)-2-((tert-Butoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidHCID 117872809N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Product 2

HCID 131735268tert-butyl (1R)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamateHCID 131735269tert-butyl (1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2 h-pyran-4-yl)acetic acid (94.2 mg, 363 μmol, Eq: 2) and diisopropylethylamine (127 μL, 727 μmol, Eq: 4) in DCM (2 mL) was added N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (115 mg, 436 μmol, Eq: 2.4) and the resulting solution was stirred at rt for 1 h. N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (50 mg, 182 μmol, Eq: 1.00) was added and the reaction was stirred at rt overnight. The reaction mixture was diluted with EtOAc (20 mL) and washed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH and brine and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in hexanes) to give tert-butyl (1R)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamate (48 mg) and tert-butyl (1S)-2-(2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2 h-pyran-4-yl)ethylcarbamate (46 mg), m/z=517 (M+H).

Workup

  1. stirringthe reaction was stirred at rt overnight
  2. washwashed with 0.1 M aqueous KHSO4, 0.1 M aqueous NaOH and brine
  3. concentrationconcentrated in vacuo
  4. customThe crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-7e2f6f363de54ae5bc53873988974a8f
Source dataset
uspto-grants-2016_04
Patent number
US09309248B2

Reaction notes

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