Dichloromethane → 4-Chloro-5-(3-chloropyridin-4-yl)pyridin-2-amine

Temperature

60 °C

4-Chloro-5-iodopyridin-2-amine (8.100 g, 31.8 mmol), sodium carbonate (5.00 g, 47.7 mmol), and 3-chloropyridin-4-ylboronic acid hydrate (11.2 g, 63.7 mmol) were combined in 100 mL of 1,4-Dioxane and 25 mL of water. Nitrogen was bubbled through the solution for ˜2 min before adding trans-dichlorobis(triphenyl-phosphine)palladium (II) (2.05 g, 2.92 mmol). The solution was heated to 60° C. overnight. Additional trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.2 g, 0.285 mmol), 3-chloropyridin-4-ylboronic acid hydrate (4.00 g, 22.8 mmol), 15 mL of water (degassed) and sodium carbonate (1.75 g, 16.6 mmol) were added. The solution was heated to 100° C. for 5 hours. Additional 3-chloropyridin-4-ylboronic acid hydrate (4.00 g, 22.8 mmol) was added and the reaction continued for 2 h at 100° C. The solution was concentrated under vacuum to ⅕th the volume and extracted between DCM and water. The aqueous layer was extracted with 10% isopropanol/DCM. The combined organics were dried over MgSO4 and then concentrated under vacuum to give an orange solid. The solid was slurried with DCM and then filtered through a fitted funnel. The solids were washed with additional DCM. The combined filtrate was purified on a 80 g Combiflash column (dry loaded), eluting with 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 8% methanol/0.4% NH4OH (˜28% in water)/DCM. The fractions containing the product were concentrated under vacuum to give a yellowish solid. The solids were triturated with DCM to give 4-chloro-5-(3-chloropyridin-4-yl)pyridin-2-amine (3.93 g, 51%) as an off white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.73 (1 H, s), 8.58 (1 H, d, J=4.9 Hz), 7.87 (1 H, s), 7.44 (1 H, d, J=4.9 Hz), 6.64 (1 H, s), 6.55 (2 H, br. s.); LCMS-ESI (POS), M/Z, M+1: Found 239.9.

1. customNitrogen was bubbled through the solution for ˜2 min
2. temperatureThe solution was heated to 100° C. for 5 hours
3. concentrationThe solution was concentrated under vacuum to ⅕th the volume
4. extractionextracted between DCM and water
5. extractionThe aqueous layer was extracted with 10% isopropanol/DCM
6. dry with materialThe combined organics were dried over MgSO4
7. concentrationconcentrated under vacuum
8. customto give an orange solid
9. filtrationfiltered through a fitted funnel
10. washThe solids were washed with additional DCM
11. customThe combined filtrate was purified on a 80 g Combiflash column (dry loaded)
12. washeluting with 2% methanol/0.1% NH4OH (˜28% in water)/DCM to 8% methanol/0.4% NH4OH (˜28% in water)/DCM
13. additionThe fractions containing the product
14. concentrationwere concentrated under vacuum
15. customto give a yellowish solid
16. customThe solids were triturated with DCM

ORD record

ord-9af3c4a2aeae488faf67ca06643cf74d

Source dataset

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08980903B2