Tetrafluoroboric acid → HCID 86715515, compound

Temperature

90 °C

6-(2-chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (2.0 g, 7.3 mmol), 3-chloro-4-fluoro-phenylboronic acid (2.5 g, 14.3 mmol), KF (2.5 g, 43.0 mmol) and 1,4-dioxane (75 mL) and stir bar were added to a reaction flask. The contents were degassed by vacuum and back filled with argon three times while stirring. Subsequently, commercially available catalyst Pd2(dba)3.t-Bu3P.HBF4 (1:2) (1 g, 0.67 mmol) was added to the reaction contents, repeated degassing cycles and heated at 90° C. under argon. Colorimetric changes were observed after the introduction of catalyst and as the reaction progressed from pale pink to yellow to off-green slurries. After 6 h, the reaction stirring was stopped, filtered the hot slurry and washed the cake with additional amount of dioxane (30 mL). The pale yellow clear filtrate solution was passed through a pad of Celite® and concentrated the filtrate. The crude solid residue was partitioned between CH2Cl2 (150 mL)/water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate was stirred in 60% EtOAc/hexanes (30 mL), suction filtered and dried the solid to obtain 1.6 g of (purity: 95%) 6-(2-(3-chloro-4-fluorophenyl)pyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine as an off-white solid. The filtrate was concentrated and purified the concentrate by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 0-30-60% EtOAC/hexanes eluting solvent gradient) to obtain additional 0.65 of titled compound.

1. additionwere added to a reaction flask
2. customThe contents were degassed by vacuum
3. additionback filled with argon three times
4. customrepeated degassing cycles
5. stirringthe reaction stirring
6. filtrationfiltered the hot slurry
7. washwashed the cake with additional amount of dioxane (30 mL)
8. concentrationconcentrated the filtrate
9. customThe crude solid residue was partitioned between CH2Cl2 (150 mL)/water (50 mL)
10. customThe organic layer was separated
11. dry with materialdried over MgSO4
12. filtrationfiltered
13. concentrationconcentrated
14. concentrationThe crude concentrate
15. stirringwas stirred in 60% EtOAc/hexanes (30 mL)
16. filtrationsuction filtered
17. customdried the solid

ORD record

ord-a305b5b3b77c4992b56bc21c028e0deb

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09145433B2