Acetonitrile--water (1/1) → (R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate

HRID 408331Notes

Reaction equation

HRID 408331 reaction equation
[CH3:1][N:2]([C@@H:10]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:16][C:17]1[C:18](F)=[C:19]2[C:25]([NH:26][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.CC#N.O>CCCCO.O>[Br:16][C:17]1[C:18]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]2)=[C:19]2[C:25]([NH:26][C:27](=[O:31])[CH:28]([CH3:29])[CH3:30])=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1

Participants

6

Reactant 3

HCID 18373917Acetonitrile--water (1/1)HCID 28875356tert-Butyl methyl((3R)-piperidin-3-yl)carbamateHCID 60205321N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Product 1

HCID 67045518(R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamateYield 13.2%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 962WaterSolvent

Conditions

Temperature
160 °C

Procedure

(R)-tert-Butyl methyl(piperidin-3-yl)carbamate (471 mg, 2.20 mmol; Example E) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (220 mg, 0.733 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tube at 160° C. for 24 hours. The cooled mixture was diluted with water (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-90% CH3CN/water, 25CV) to give (R)-tert-butyl 1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (48 mg, 13% yield) as a solid. LCMS (APCI+) m/z 494.1, 497.1 (M+H)+, Retention time=4.18 minutes.

Workup

  1. extractionextracted with EtOAc (3×20 mL)
  2. dry with materialThe combined organic layer was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified by reverse phase chromatography (Biotage SP4

Sources & evidence

ORD record
ord-d1594c46a63a4e2cad88efa4abb80315
Source dataset
uspto-grants-2014_06
Patent number
US08758830B2

Reaction notes

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