Ammonia → HCID 58020095, compound

Temperature

2.5 °C

To a cooled (0-5° C.) and stirred solution of (S)-1-[5-(3′-chloro-2-fluoro-6methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid (I-143, 0.22 g, 0.54 mmol) in THF (2.5 mL) was added N,N-diisopropylethylamine (0.07 g, 0.57 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.08 g, 0.57 mmol) was added, stirred at 0-5° C. for 45 min. Ammonia in methanol (7M sol, 1.0 mL, 7.0 mmol) was added, the reaction warmed to room temperature, and stirred for 0.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane, followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.06 g (27%) of P-615 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.99 (d, J=2.8 Hz, 1H), 7.51 (br s, 1H), 7.34-7.46 (m, 4H), 7.24-7.3 (m, 2H), 7.14 (br s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.39 (dd, J=9.6, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.8 (s, 2H), 3.72 (s, 3H), 2.26-2.48 (m, 2H) ppm;

1. stirringstirred at 0-5° C. for 45 min
2. temperaturethe reaction warmed to room temperature
3. stirringstirred for 0.5 h
4. customThe organic layer was separated
5. extractionthe aqueous layer was extracted with ethyl acetate (2×20 mL)
6. dry with materialThe combined organic layers were dried with Na2SO4
7. filtrationfiltered
8. concentrationconcentrated
9. customThe residue was purified by silica gel column chromatography
10. customto afford 0.06 g (27%) of P-615 as an off-white solid

ORD record

ord-36a43603be9e412e84d69d358784bad2

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08791267B2