Dichloromethane → HCID 15603652, compound

Temperature

70 °C

To a flame-dried round bottom flask was placed 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (44 mg, 0.1 mmol), 4-chlorophenylboronic acid (31 mg, 0.2 mmol), K3PO4 (42.5 mg, 0.2 mmol) and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II), complex with CH2Cl2 (1:1) (16 mg, 0.02 mmol). The flask was purged with argon for 15 min before addition of degassed anhydrous THF (1 mL). The reaction mixture was stirred at 70° C. under argon for 16 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL), washed with 1 N aqueous NaOH, water, saturated aqueous NaCl, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 8 min gradient, hold at 100% B for 6 min (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The yellow residue was dissolved in acetonitrile, frozen and lyophilized to afford 18.2 mg (35%) of the title compound as a yellow powder. LC/MS (method A): retention time=3.94 min, (M+H)+=516. 1H NMR (CDCl3, 400 MHz): δ 8.83 (d,J=1.71 Hz, 1H), 7.98 (dd, J=7.95, 2.08 Hz, 1H), 7.69 (d,J=8.07 Hz, 1H), 7.41 (s, 1H), 7.25-7.32 (m, 4H), 7.20-7.23 (m, 2H), 7.00-7.04 (m, 2H), 5.33 (s, 2H).

1. customTo a flame-dried round bottom flask was placed
2. customThe flask was purged with argon for 15 min before addition of degassed anhydrous THF (1 mL)
3. temperatureAfter cooling to room temperature
4. additionthe reaction mixture was diluted with EtOAc (20 mL)
5. washwashed with 1 N aqueous NaOH, water, saturated aqueous NaCl
6. dry with materialdried (Na2SO4)
7. concentrationconcentrated under reduced pressure
8. customThe crude product was purified
9. washEluted with 60% to 100% B, 8 min gradient
10. waithold at 100% B for 6 min
11. concentrationThe desired fractions were concentrated under reduced pressure
12. dissolutionThe residue was dissolved in EtOAc
13. washwashed with saturated aqueous NaHCO3 once
14. dry with materialwater twice, then saturated aqueous NaCl, dried over Na2SO4
15. customevaporated
16. dissolutionThe yellow residue was dissolved in acetonitrile
17. temperaturefrozen

ORD record

ord-ca0ecb9e4749473d81bb1502413ba0be

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07317012B2