Potassium Phosphate, Tribasic → HCID 68358954, compound

Temperature

90 °C

A solution of 6-bromo-4-((1R,3S)-3-carbamoyl-2,2,3-trimethylcyclopentylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (50 mg, 0.122 mmol) in DMF (816 μl) was added into a reaction vial charged with 6-methoxypyridin-3-ylboronic acid (37.5 mg, 0.245 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene (5.88 mg, 0.012 mmol) and palladium (II) acetate (2.75 mg, 0.012 mmol), followed by addition of a 2.0 M aqueous potassium phosphate, dibasic solution (184 μl, 0.367 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 90° C. for 2 hrs. The reaction was cooled to room temperature and diluted with ethyl acetate (10 ml). The ethyl acetate solution was washed with water (3×5 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a light yellow oil. The crude product was chromatographed using reverse-phase HPLC (Column: LUNA 5u C18 21×100). The collected fractions were combined and concentrated under reduced pressure. The product was taken up in ethyl acetate and neutralized with (sat.) sodium carbonate. The ethyl acetate extract was dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.3 mg, 0.025 mmol, 20.08% yield) as a white solid. LC/MS found [M+H]+=437.3. 1H NMR (400 MHz, MeOD) δ ppm 8.42-8.48 (1 H, m), 8.11-8.18 (1 H, m), 7.96-8.04 (1 H, m), 7.89-7.96 (1 H, m), 7.10-7.19 (1 H, m), 6.84-6.91 (1 H, m), 4.66-4.74 (1 H, m), 3.94 (3 H, s), 2.53-2.65 (1 H, m), 2.41-2.53 (1 H, m), 1.69-1.81 (1 H, m), 1.57-1.69 (1 H, m), 1.34-1.42 (3 H, m), 1.11-1.18 (3 H, m), 1.02-1.11 (3 H, m). HPLC Retention Time=2.790 (HPLC conditions: column: Phenominex Synergy, 4.6×50 mm, Mobile phase A: 90:10 water/methanol with 0.2% H3PO4; Mobile Phase B: 90:10 methanol/water with 0.2% H3PO4; Wavelength: 220 nm; Gradient: 0-100% B over 4 minutes, then a 1-minute hold at 100% B; Flow: 4 mL/min.)

1. customThe suspension was purged with nitrogen for 5 minutes
2. customThe vial was sealed
3. temperatureThe reaction was cooled to room temperature
4. additiondiluted with ethyl acetate (10 ml)
5. washThe ethyl acetate solution was washed with water (3×5 ml)
6. dry with materialdried with sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customyielding a light yellow oil
10. customThe crude product was chromatographed
11. concentrationconcentrated under reduced pressure
12. extractionThe ethyl acetate extract
13. dry with materialwas dried with sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated under reduced pressure

ORD record

ord-3f0cca9e051049b299aeaa288822423b

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921368B2