Reaktion #495507

Reaktionsgleichung

TFA

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

Ausbeute 56.0%

Lösungsmittel

n-BuOH

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe solvent was removed
2. 2
   workup.DISSOLUTIONthe resulting 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
   workup.STIRRINGThe mixture was stirred at room temperature for 1 hour
10. 10
    SonstigeThe solvent was removed
11. 11
    workup.DISSOLUTIONThe residue was dissolved in MeOH (1 mL)
12. 12
    workup.ADDITION2N HCl in ether (3 mL) was added
13. 13
    SonstigeThe solid formed
14. 14
    Filtrationwas collected by filtration

Vorschrift

A mixture of N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (50 mg, 0.18 mmol; Example 13, Step D), tert-butyl 3-methylpiperidin-3-ylcarbamate (78 mg, 0.37 mmol, Example C) and DIEA (0.032 mL, 0.182 mmol) in n-BuOH (1 mL) was stirred at 150° C. (bath) for 24 hours in a sealed tube. The solvent was removed, and the resulting 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 removed. The residue was dissolved in MeOH (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-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.050 g, 56%) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 11.03 (s, 1H), 9.49 (s, 1H), 8.95 (m, 2H), 8.27 (s, 2H), 8.18 (d, 1H), 7.93 (m, 1H), 7.53 (d, 1H), 3.43 (m, 1H), 3.36 (m, 2H), 3.04 (m, 1H), 1.71 (m, 1H), 1.51 (m, 2H), 1.31 (m, 1H), 1.22 (s, 3H). LCMS (APCI+) m/z 369 (M+H)+.

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