Reaktion #2000649

Reaktionsgleichung

5-chloropyrazine-2-carbonitrile

K2CO3

tert-butyl 2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

bis(pinacolato)diboron

potassium acetate

→

title compound

Ausbeute 59.5%

tert-Butyl 2-((R)-5-(5-cyanopyrazin-2-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Ausbeute 59.5%

Lösungsmittel

dioxane

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe mixture was purged with nitrogen for 15 minutes
2. 2
   Sonstigethe reaction mixture was purged with nitrogen for an additional 15 minutes
3. 3
   Sonstigethe complete consumption of the starting material (3-1a)
4. 4
   TemperaturThe reaction was cooled to room temperature
5. 5
   workup.ADDITIONto addition)
6. 6
   workup.ADDITIONwere added
7. 7
   SonstigeThe reaction was purged with nitrogen (3×)
8. 8
   Temperaturwas heated for 20 hours at 110° C
9. 9
   TemperaturThe reaction was cooled
10. 10
    Einengenconcentrated in vacuo
11. 11
    SonstigeThe residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution
12. 12
    WaschenThe organics layer was washed with 50 mL of brine
13. 13
    Trocknendried (Na2SO4)
14. 14
    Einengenconcentrated
15. 15
    Sonstigeto give crude product as black semi-solid
16. 16
    SonstigeThe crude product was purified via silca gel chromatography
17. 17
    Sonstigea Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) system
18. 18
    Wascheneluting with 0-100% EtOAc

Vorschrift

To a solution of tert-butyl 2-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 700 mg, 1.66 mmol) in anhydrous dioxane (10 mL) was added bis(pinacolato)diboron (473 mg, 1.86 mmol) and potassium acetate (659 mg, 6.71 mmol). The mixture was purged with nitrogen for 15 minutes. Pd(dppf)Cl2 (62 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen for an additional 15 minutes. The reaction was heated to 110° C. under nitrogen for 5 hours. TLC indicated the complete consumption of the starting material (3-1a). The reaction was cooled to room temperature and 5-chloropyrazine-2-carbonitrile (278 mg, 1.99 mmol), Pd(dppf)Cl2 (62 mg, 0.07 mmol) and 5.81 mL of 2M aqueous K2CO3 solution (de-oxygenated with a stream of nitrogen for 15 minutes prior to addition) were added. The reaction was purged with nitrogen (3×) and was heated for 20 hours at 110° C. The reaction was cooled and concentrated in vacuo. The residue was partitioned between 50 mL of ethyl acetate and 50 mL of 1N NaOH solution. The organics layer was washed with 50 mL of brine, dried (Na2SO4) and concentrated to give crude product as black semi-solid. The crude product was purified via silca gel chromatography using a Combiflash ISCO purification system (Teledyne Corp., Lincoln, Nebr.) system, eluting with 0-100% EtOAc:heptanes to give the title compound as a brown solid (440 mg, 59%). MS (ES+) 446.3 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.56-1.64 (m, 4H), 1.81-1.92 (m, 1H), 2.06 (dd, 1H), 2.77-2.87 (m, 1H), 2.92-3.04 (m, 3H), 3.12 (d, 2H), 3.24-3.28 (m, 4H), 3.86 (dd, 1H), 7.41 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 1H), 8.09 (s, 1H), 8.90 (s, 1H).

Quelle