Reaktion #84143

Reaktionsgleichung

5-bromo-2-methoxy-nicotinonitrile

bis(pinacolato)diboron

potassium acetate

2,4 dichloropyrimidine

sodium carbonate

boronic acid

→

desired compound

Ausbeute 51.9%

5-(2-Chloro-pyrimidin-4-yl)-2-methoxy-nicotinonitrile

Ausbeute 51.9%

Lösungsmittel

water

1,4-dioxane

1,4-dioxane

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe reaction mixture was deoxygenated with argon, Pd(dppf)Cl2
2. 2
   workup.ADDITIONwas added
3. 3
   TemperaturThe reaction mixture was cooled to rt
4. 4
   workup.ADDITIONdiluted with water (100 mL)
5. 5
   Filtrationfiltered through Celite
6. 6
   ExtraktionThe filtrate was extracted with EtOAc (2×150 mL)
7. 7
   Trocknenthe combined organic layer dried over Na2SO4
8. 8
   Sonstigeevaporated
9. 9
   Sonstigeto obtained a crude mixture
10. 10
    workup.ADDITIONcontaining
11. 11
    SonstigeThe reaction mixture was deoxygenated with argon gas, Pd(PPh3)4
12. 12
    workup.ADDITIONwas added
13. 13
    Sonstigeagain deoxygenated for 30 min
14. 14
    TemperaturThe resulting mixture was heated at 100° C. for 3 h
15. 15
    TemperaturThe reaction mixture was cooled to rt
16. 16
    workup.ADDITIONdiluted with water (100 mL)
17. 17
    Extraktionextracted with EtOAc (3×100 mL)
18. 18
    Trocknenthe combined organic layer was dried (Na2SO4)
19. 19
    Sonstigeevaporated
20. 20
    SonstigeThe crude compound was purified by flash column chromatography (100-200 mesh silica gel)
21. 21
    Wascheneluting with 30% EtOAc/pet ether

Vorschrift

To a stirred solution of 5-bromo-2-methoxy-nicotinonitrile (10 g, 46.9 mmol) and bis(pinacolato)diboron (17.9 g, 70.4 mmol) in 1,4-dioxane (300 mL) was added potassium acetate (13.8 g, 140.8 mmol). The reaction mixture was deoxygenated with argon, Pd(dppf)Cl2 was added and the mixture deoxygentated for a further 20 min. The resulting mixture was heated at 100° C. for 1.5 h. The reaction mixture was cooled to rt, diluted with water (100 mL) and filtered through Celite. The filtrate was extracted with EtOAc (2×150 mL), the combined organic layer dried over Na2SO4 and evaporated to obtained a crude mixture containing an approximate 1:1 mixture of boronic ester and boronic acid (12 g). The crude material was dissolved in 1,4-dioxane (100 mL) and 2,4 dichloropyrimidine (8.4 g, 56.2 mmol) was added followed by a solution sodium carbonate (17.9 g, 168.5 mmol) in water (25 mL). The reaction mixture was deoxygenated with argon gas, Pd(PPh3)4 was added and again deoxygenated for 30 min. The resulting mixture was heated at 100° C. for 3 h. The reaction mixture was cooled to rt, diluted with water (100 mL), extracted with EtOAc (3×100 mL), the combined organic layer was dried (Na2SO4) and evaporated. The crude compound was purified by flash column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to obtain the desired compound (6 g, 51% (over two steps)) as a white solid; Rf: 0.3 (40% EtOAc/pet ether); (m/z): 247[M+1]+; 1H NMR (300 MHz, DMSO-d6): δ 9.24 (1H, d, J=2.4 Hz), 8.98 (1H, d, J=2.1 Hz), 8.89 (1H, d, J=5.1 Hz), 8.21 (1H, d, J=5.1 Hz), 4.04 (3H, s). 2-Methoxy-5-[2-(6-morpholin-4-ylmethyl-pyridin-3-ylamino)-pyrimidin-4-yl]-nicotinonitrile (17)

Quelle