Trifluoroacetic acid → 6-(3-Cyano-5-(trifluoromethyl)phenylamino)-8-(isopropylamino)imidazo[1,2-b]pyridazine-3-carbonitrile

Temperature

125 °C

A solution of 3-amino-5-(trifluoromethyl)benzonitrile (0.078 g, 0.42 mmol) in DMA (1 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was purged with argon. 10A (0.100 g, 0.281 mmol), cesium carbonate (0.366 g, 1.124 mmol), copper(I) iodide (0.027 g, 0.141 mmol), Xantphos (0.033 g, 0.056 mmol), and Pd2(dba)3 (0.026 g, 0.028 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was then heated to 125° C. for 45 min. The solids were removed via filtration through CELITE® and washed with THF. The dark brown filtrate was concentrated under reduced pressure and then diluted with water and ethyl acetate. The layers were separated, and the aqueous phase extracted with ethyl acetate (2×10 mL). The organics were combined, washed with water and brine, dried over sodium sulfate, filtered, concentrated, and the residue was purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm). The fractions were concentrated, dissolved in DCM (1 mL), and treated with triethylsilane (0.45 mL, 2.8 mmol), and TFA (0.3 mL) at room temperature. After 20 min., the volatiles were removed via a stream of nitrogen. The residue was triturated with MeOH, forming a white precipitate. The solid was isolated via filtration, washed with MeOH, and suspended in 1:1 1N HCl/MeCN and lyophilized, affording Example 10, (0.081 g, 68.3% yield) as a white solid. HPLC: Rt=4.35 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=386.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 8.52 (1H, s), 8.24 (1H, s), 8.19 (1H, s), 7.82 (1H, s), 7.48 (1H, d, J=8.03 Hz), 5.94 (1H, s), 2.52-2.55 (1H, m), 1.28 (6H, d, J=6.27 Hz).

1. customcap
2. customthe solvent was purged with argon
3. customthe suspension was pump/purged three times with argon
4. customThe solids were removed via filtration through CELITE®
5. washwashed with THF
6. concentrationThe dark brown filtrate was concentrated under reduced pressure
7. additiondiluted with water and ethyl acetate
8. customThe layers were separated
9. extractionthe aqueous phase extracted with ethyl acetate (2×10 mL)
10. washwashed with water and brine
11. dry with materialdried over sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated
14. customthe residue was purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm)
15. concentrationThe fractions were concentrated
16. dissolutiondissolved in DCM (1 mL)
17. customthe volatiles were removed via a stream of nitrogen
18. customThe residue was triturated with MeOH
19. customforming a white precipitate
20. customThe solid was isolated via filtration
21. washwashed with MeOH
22. customaffording Example 10, (0.081 g, 68.3% yield) as a white solid

ORD record

ord-f7f31a5e15014ed285f6438f3fa48921

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08252795B2