Reaktion #495506

Reaktionsgleichung

TFA

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

tert-butyl 3-methylpiperidin-3-ylcarbamate

DIEA

DCM

→

N-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride

Ausbeute 8.0%

Lösungsmittel

n-BuOH

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe solvent was removed
2. 2
   workup.DISSOLUTIONthe residue was dissolved in ethyl acetate (20 mL)
3. 3
   Waschenwashed with water (10 mL), brine (10 mL)
4. 4
   Trocknendried (sodium sulfate)
5. 5
   Einengenconcentrated in vacuo
6. 6
   SonstigeThe residue obtained
7. 7
   Sonstigewas purified by C-18 reverse phase flash chromatography (Biotage SP4 unit
8. 8
   SonstigeThe product isolated
9. 9
   SonstigeThe solvent was then removed
10. 10
    workup.DISSOLUTIONThe residue was dissolved in DCM (1 mL)
11. 11
    workup.ADDITION2N HCl in ether (3 mL) was added
12. 12
    SonstigeThe solid formed
13. 13
    Filtrationwas collected by filtration

Vorschrift

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.298 mmol), tert-butyl 3-methylpiperidin-3-ylcarbamate (192 mg, 0.895 mmol) and DIEA (0.052 mL, 0.298 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried (sodium sulfate), and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M+ column, 10-80% CH3CN/water gradient; 30 CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was then removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give N-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (12.8 mg, 7.96% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.09 (s, 1H), 10.54 (s, 1H), 9.37 (s, 1H), 8.91 (d, 1H), 8.70 (m, 1H), 8.29 (s, 1H), 8.05 (s, 3H), 7.83 (m, 1H), 7.54 (s, 1H), 3.40 (m, 2H), 3.27 (m, 1H), 3.17 (m, 2H), 1.65 (m, 2H), 1.46 (m, 1H), 2.00 (s, 3H); LCMS (APCI+) m/z 429 (M+H)+.

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