Reaktion #1018396

Reaktionsgleichung

triethylamine

(R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride

acetic acid

ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate

→

(R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone

Ausbeute 94.7%

Lösungsmittel

ethanol

ethanol

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe resulting mixture was purged with nitrogen
2. 2
   TemperaturThe mixture was cooled to room temperature
3. 3
   Sonstigethe solvent was removed under reduced pressure
4. 4
   SonstigeThe residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and dichloromethane (50 mL)
5. 5
   ExtraktionThe aqueous layer was extracted with dichloromethane (50 mL)
6. 6
   WaschenThe combined organics were washed with a saturated aqueous solution of sodium bicarbonate
7. 7
   Extraktionthe resulting aqueous layer was extracted with dichloromethane (50 mL)
8. 8
   Waschenwashed with brine
9. 9
   Trocknendried over sodium sulfate
10. 10
    Filtrationfiltered
11. 11
    Einengenconcentrated under reduced pressure
12. 12
    SonstigeThe crude material was purified via flash chromatography (0-5% methanol in dichloromethane)

Vorschrift

To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (5.5 g, 15.2 mmol) and acetic acid (17.4 mL, 305 mmol) in ethanol (20 mL) was added a solution of ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (3.25 g, 15.2 mmol) in ethanol (30 mL) followed by triethylamine (12.7 mL, 91.2 mmol). The resulting mixture was purged with nitrogen. The reaction mixture was stirred for 18 h at 100° C. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL). The combined organics were washed with a saturated aqueous solution of sodium bicarbonate and the resulting aqueous layer was extracted with dichloromethane (50 mL). The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-5% methanol in dichloromethane) to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (6.33 g, 94%). 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; UPLC retention time 0.47 min (Method N).

Quelle