Hexane → HCID 86641425, compound

Temperature

-78 °C

To a solution of 1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (14 mg, 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) at −78° C. in a dry flask equipped with an inlet of dry nitrogen was added fresh 1.6 M n-butyl lithium in n-hexane (40 μL, 0.06 mmol) with stirring. The reaction mixture was stirred at −78° C. for 30 minutes, then at 0° C. for 1 hour. The reaction mixture was re-cooled to −78° C., a solution of tert-butyl bromoacetate (98 mg, 0.50 mmol) in anhydrous tetrahydrofuran added (0.5 mL), and the reaction mixture stirred overnight, allowing it to warm up to room temperature. The reaction was followed by LCMS, and stirring was continued as needed until the starting material was consumed. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL) with stirring, concentrated under reduced pressure, diluted with ethyl acetate (10 mL) and diluted with aqueous ammonium chloride (5 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL), and the combined organic phase was successively washed with 2N sodium carbonate (10 mL), 30% ammonium chloride (10 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave a crude mixture which was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford tert-butyl 2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (12 mg, 0.02 mmol, 67%). LCMS mz 524.0 (M-tBu), 602.0 (M+Na), anal HPLC>98% in purity. 1H NMR (400 MHz; acetone-d6) δ7.77 (t, J=8.0 Hz, 1H); 7.60 (m, 2H); 7.38 (m, 2H); 7.11 (m, 1H); 7.00 (m, 1H); 6.81 (s, 1H); 5.35 (s, 2H); 3.80 (s, 3H); 2.70-3.30 (m, 3H); 2.40-2.60 (m, 2H); 1.48 (s, 9H).

1. stirringThe reaction mixture was stirred at −78° C. for 30 minutes
2. stirringthe reaction mixture stirred overnight
3. temperatureto warm up to room temperature
4. stirringstirring
5. customwas consumed
6. customThe reaction mixture was quenched by addition of saturated aqueous ammonium chloride (5 mL)
7. stirringwith stirring
8. concentrationconcentrated under reduced pressure
9. additiondiluted with ethyl acetate (10 mL)
10. additiondiluted with aqueous ammonium chloride (5 mL)
11. extractionThe aqueous phase was extracted with ethyl acetate (3×10 mL)
12. washthe combined organic phase was successively washed with 2N sodium carbonate (10 mL), 30% ammonium chloride (10 mL), brine (20 mL)
13. dry with materialdried over magnesium sulfate
14. customEvaporation of the solvent under reduced pressure
15. customgave a crude mixture which
16. customwas purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%)

ORD record

ord-ab9afae9e36d4080a4545c4e2271228c

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08664379B2