Reaktion #163047

Reaktionsgleichung

(R)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile

(R)-6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile

HCl

→

title compound

Ausbeute 57.0%

(R)-2-(3-(Aminomethyl)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoropyridin-2-ylamino)-2-(4-fluorophenyl)ethanol

Ausbeute 57.0%

Lösungsmittel

MeOH

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigewas flushed with N2
2. 2
   Sonstigeevacuated
3. 3
   SonstigeThe reaction was then evacuated
4. 4
   Sonstigeflushed with N2
5. 5
   Filtrationfiltered
6. 6
   Waschenwashed with MeOH (3×30 ml)
7. 7
   Einengenconcentrated
8. 8
   workup.DISSOLUTIONThe resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml)
9. 9
   workup.ADDITIONa saturated aqueous solution of Na2CO3 (100 ml) was added
10. 10
    Sonstigeto separate
11. 11
    ExtraktionThe aqueous layer was extracted with DCM (3×100 ml)
12. 12
    SonstigeThe combined organic layer was dried
13. 13
    Filtrationfiltered
14. 14
    Einengenconcentrated
15. 15
    SonstigeThe resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml)

Vorschrift

The mixture of (R)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)-2-hydroxyethylamino)nicotinonitrile (Example 6; 0.13 g, 0.33 mmol), conc. HCl (0.1 ml), and Pd (10 wt. %, dry basis, on activated carbon, 0.12 g) in MeOH (5 ml) was flushed with N2, evacuated, and then placed under H2 (40 psi) for 6 hrs. The reaction was then evacuated, flushed with N2, filtered, washed with MeOH (3×30 ml), and concentrated. The resulting solid was dissolved in the mixture of DCM-MeOH (50:1, 100 ml), and a saturated aqueous solution of Na2CO3 (100 ml) was added. The mixture was shaken vigorously for 30 min and allowed to separate. The aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was dried, filtered and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.074, 57%). 1H NMR (400 MHz, CD3OD) δ 7.45-7.42 (m, 2H), 7.17 (d, J=11.1 Hz, 1H), 7.04-7.00 (m, 2H), 5.72 (br s, 1H), 5.18-5.08 (m, 1H), 3.89-3.72 (m, 4H), 1.87-1.83 (m, 1H), 0.94-0.92 (m, 2H), 0.69-0.65 (m, 2H). MS: Calcd.: 400. Found: [M+H]+401.

Quelle