Methanol → HCID 89783180, compound

Similar to the procedure described in Example 103, rac-1,1,1,-trifluoro-2-propanol (Aldrich Chemical Company; 0.18 mL, 2.02 mmol) was added to a suspension of NaH (60% w/w in mineral oil) (81 mg, 2.02 mmol) in DMF (2.0 mL) and the resulting light-green solution was stirred at RT for 10 min. 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 75 mg, 0.25 mmol) was then added and the resulting dark red solution was stirred at RT for 5 min, then heated at 70° C. for 2.5 h. The mixture was cooled to RT and partitioned between EtOAc (70 mL) and saturated aq. NH4Cl (50 mL). The organic layer was separated, sequentially washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO (2.5 mL) and purified by reverse-phase using HPLC (Silicycle column, 20-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min), then dried in a Genevac Series II Evaporator. The residue was chromatagraphically purified then (silica gel; 0-10% MeOH in DCM) affording rac-2-(2-((1,1,1-trifluoropropan-2-yl)oxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16.0 mg, 0.043 mmol, 16.9% yield) as an amorphous yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (br. s., 1H), 8.39 (d, J=8.8 Hz, 1H), 7.96 (d, J=6.8 Hz, 1H), 7.82 (d, J=7.2 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 6.95 (br. s., 1H), 6.09 (dt, J=13.5, 6.8 Hz, 1H), 3.40-3.49 (m, 2H), 2.87 (t, J=6.7 Hz, 2H), 1.57 (d, J=6.7 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm −77.03 (s, 3F). m/z (ESI, +ve ion) 376.0 (M+H)+.

1. stirringthe resulting dark red solution was stirred at RT for 5 min
2. temperatureheated at 70° C. for 2.5 h
3. temperatureThe mixture was cooled to RT
4. custompartitioned between EtOAc (70 mL) and saturated aq. NH4Cl (50 mL)
5. customThe organic layer was separated
6. washsequentially washed with water (20 mL) and brine (20 mL)
7. dry with materialdried over MgSO4
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. dissolutionThe residue was dissolved in DMSO (2.5 mL)
11. custompurified by reverse-phase
12. customHPLC (Silicycle column, 20-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min)
13. dry with materialdried in a Genevac Series II Evaporator
14. customThe residue was chromatagraphically purified

ORD record

ord-f394a5a791a34359b65f713ad89f42b4

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09394297B2