反応 #157156

反応方程式

2-bromo-3-fluoropyridine

3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide

bis(pinacolato)diboron

PCy3

KOAc

→

5-amino-N-(2′-amino-6′-methyl-4,4′-bipyridin-3-yl)-3′-fluoro-2,2′-bipyridine-6-carboxamide

溶媒

EtOAc

H2O

dioxane

反応条件

後処理

1. 1
   その他was consumed
2. 2
   ろ過Filtered
3. 3
   その他the reaction
4. 4
   濃縮concentrated the filtrate
5. 5
   その他The crude was dried under vacuo
6. 6
   workup.DISSOLUTIONdissolved in DME/2M Na2CO3 (3:1, 0.05M)
7. 7
   温度Cooled to room temperature
8. 8
   洗浄the organic phase was washed with brine
9. 9
   乾燥dried with Na2SO4
10. 10
    濃縮concentrated
11. 11
    その他The crude material was purified via SiO2 column chromatography
12. 12
    洗浄eluting with EtOAc and hexanes (1:1)
13. 13
    濃縮the pure product was concentrated
14. 14
    濃縮The reaction was concentrated to dryness
15. 15
    その他purified via reverse phase HPLC

実験手順

To a solution of degassed dioxane (0.03M) was added 3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide (1.0 equiv.), bis(pinacolato)diboron (2.0 equiv.), Pd2(dba)3 (0.05 equiv.), PCy3 (0.075 equiv.), and KOAc (3.0 equiv.). The solution was heated to 90° C. for 16 hrs until all starting material was consumed. Filtered the reaction and concentrated the filtrate. The crude was dried under vacuo, then dissolved in DME/2M Na2CO3 (3:1, 0.05M), followed by addition of 2-bromo-3-fluoropyridine (2.0 equiv.) and Pd(dppf)Cl2-DCM (0.10 equiv.). The reaction was heated to 100° C. in an oil bath until consumption of the boronic ester. Cooled to room temperature, added H2O and EtOAc, the organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude material was purified via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) and the pure product was concentrated and stirred in DCM/TFA (25%) until completion of the deprotection. The reaction was concentrated to dryness and purified via reverse phase HPLC to afford 5-amino-N-(2′-amino-6′-methyl-4,4′-bipyridin-3-yl)-3′-fluoro-2,2′-bipyridine-6-carboxamide. LCMS (m/z): 416.2 (MH+); LC Rt=1.77 min.

出典