Reaktion #976633

Reaktionsgleichung

1G

6-chloro-8-(cyclopropyl(4-methoxybenzyl)amino) imidazo[1,2-b]pyridazine-3-carbonitrile

N-(5-amino-2-methylphenyl)acetamide

xantphos

triethylsilane

TFA

→

Example 1

Ausbeute 100.5%

N-(4-methoxybenzyl)cyclopropanamine

Ausbeute 100.5%

Lösungsmittel

DCM

DMA

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigecap
2. 2
   Sonstigethe solvent was degassed
3. 3
   Sonstigeby bubbling argon through it for 10 minutes
4. 4
   Sonstigethe suspension was pump/purged three times with argon
5. 5
   Temperaturcooled to room temperature
6. 6
   SonstigeThe solids were removed via filtration through CELITE®
7. 7
   Waschenwashing with THF
8. 8
   workup.ADDITIONThe filtrate was then diluted with water and EtOAc
9. 9
   SonstigeThe layers were separated
10. 10
    Extraktionthe aqueous phase extracted EtOAc (3×10 mL)
11. 11
    Waschenwashed with water and brine
12. 12
    Trocknendried over anhydrous sodium sulfate
13. 13
    FiltrationFiltration and concentration
14. 14
    Sonstigeafforded a tan solid, which
15. 15
    Sonstigewas triturated in DCM
16. 16
    Temperaturcooled to 0° C
17. 17
    FiltrationThe resulting precipitate was filtered
18. 18
    Waschenwashed with cold DCM
19. 19
    workup.DISSOLUTIONThe filtrate was dissolved in a small amount of DCM
20. 20
    Sonstigepurified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm)
21. 21
    Einengenconcentrated under reduced pressure
22. 22
    SonstigeThe material isolated from chromatography
23. 23
    Temperaturthe suspension was cooled in an ice bath
24. 24
    Filtrationfiltered
25. 25
    workup.WAITAfter 30 minutes
26. 26
    Sonstigethe solid was isolated via filtration
27. 27
    Waschenwashed with water and EtOAc
28. 28
    Sonstigedried overnight in vacuo

Vorschrift

DMA (1.5 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was degassed by bubbling argon through it for 10 minutes. 1G (0.15 g, 0.42 mmol), N-(5-amino-2-methylphenyl)acetamide (0.104 g, 0.636 mmol), copper(I) iodide (0.040 g, 0.212 mmol), xantphos (0.049 g, 0.085 mmol), and Pd2(dba)3 (0.039 g, 0.042 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE®, washing with THF. The filtrate was then diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted EtOAc (3×10 mL). The organics were combined, washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and concentration afforded a tan solid, which was triturated in DCM and cooled to 0° C. The resulting precipitate was filtered and washed with cold DCM. The filtrate was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, 0% EtOAc/DCM to 60% EtOAc/DCM, 24 g column, 30 mL/min, 20 min gradient, monitoring at 254 nm). The appropriate fractions were pooled and concentrated under reduced pressure. The material isolated from chromatography, and the solid were combined, suspended in DCM (3 mL) and treated with triethylsilane (0.68 mL, 4.24 mmol) and TFA (0.3 mL). After 30 minutes, the suspension was cooled in an ice bath and filtered. The solid was suspended in EtOAc (20 mL) and stirred with saturated aqueous sodium bicarbonate (15 mL). After 30 minutes, the solid was isolated via filtration, washed with water and EtOAc, and dried overnight in vacuo to afford Example 1 (0.154 g, 0.422 mmol, 100%) as a white solid. HPLC: Rt=3.496 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). MS (ES): m/z=362.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (1H, s), 9.21 (1H, s), 8.10 (1H, s), 7.81 (1H, s), 7.64 (2H, s), 7.11 (1H, d, J=8.03 Hz), 6.25 (1H, s), 2.52-2.55 (1H, m), 2.15 (3H, s), 2.06 (3H, s), 0.75-0.82 (2H, m), 0.61-0.68 (2H, m).

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