Reaktion #1018385

Reaktionsgleichung

diisopropylethylamine

1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid

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

O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate

Intermediate 1

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

→

(R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide

Ausbeute 53.2%

Lösungsmittel

N,N-dimethylformamide

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe solvent was removed under reduced pressure
2. 2
   workup.DISSOLUTIONthe residue was dissolved in dichloromethane
3. 3
   workup.ADDITIONA saturated aqueous solution of sodium bicarbonate was added
4. 4
   SonstigeThe organics were collected
5. 5
   Extraktionthe aqueous layer was extracted with dichloromethane
6. 6
   WaschenThe combined organics were washed with brine
7. 7
   Trocknendried over sodium sulfate
8. 8
   Filtrationfiltered
9. 9
   Einengenconcentrated under reduced pressure
10. 10
    SonstigeThe residue was purified via flash chromatography (0-12% methanol in dichloromethane)

Vorschrift

1-(3-Methylisoxazol-5-yl)cyclopropanecarboxylic acid (40 mg, 0.24 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (86 mg, 0.24 mmol), and diisopropylethylamine (200 μL, 1.2 mmol) were combined and dissolved in N,N-dimethylformamide (1.25 mL). O-Benzotriazole-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HBTU) (109 mg, 0.287 mmol) was added and the reaction mixture was stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-12% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridine-3-yl)-1-(3-methylisoxazol-5-yl)cyclopropanecarboxamide (56 mg, 53%). MS (ES+) (M+H) 439.2; LCMS retention time 1.94 min (Method L).

Quelle