反応 #1017491

反応方程式

(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

tert-butyl ((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate

3-chloro-5-(trifluoromethyl)picolinamide

intermediate 22

3-chloro-5-(trifluoromethyl)picolinamide

cesium carbonate

→

title compound

収率 13.7%

N-(6-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-5-fluoropyridin-2-yl)-3-chloro-5-(trifluoromethyl)-picolinamide

収率 13.7%

溶媒

dioxane

1,4-dioxane

反応条件

後処理

1. 1
   その他The vial was sealed
2. 2
   その他flushed with nitrogen for 10 min
3. 3
   温度The reaction mixture was cooled to RT
4. 4
   ろ過filtered through a pad of celite
5. 5
   洗浄The filter cake was washed with EtOAc
6. 6
   濃縮The filtrate was concentrated under reduced pressure
7. 7
   その他the residue was purified by reverse-phase preparative HPLC
8. 8
   その他over 25 min
9. 9
   workup.ADDITIONThe product containing fractions
10. 10
    抽出The free-based product was extracted with DCM
11. 11
    乾燥The organic phase was dried over MgSO4
12. 12
    その他the solvent was removed under reduced pressure

実験手順

A sealable vial was charged with Pd2(dba)3 (Strem, 9.03 mg, 9.86 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Strem, 22.83 mg, 0.039 mmol) and dioxane (0.5 mL). The reaction mixture was stirred under Nitrogen atmosphere for 10 min. A solution of tert-butyl ((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)carbamate (7i, 60 mg, 0.132 mmol) in 1,4-dioxane (1.3 mL), 3-chloro-5-(trifluoromethyl)picolinamide (intermediate 22, 42.8 mg, 0.191 mmol), and cesium carbonate (Aldrich, 107 mg, 0.329 mmol) were added. The vial was sealed flushed with nitrogen for 10 min and the reaction was heated to 90° C. for 3 h. The reaction mixture was cooled to RT and filtered through a pad of celite. The filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 150×30 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 70% over 25 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (9 mg, 0.018 mmol, 13.69% yield) as white solid. MS m/z=500 [M]+. Calculated for C18H13ClF7N5O2: 499.7

出典