Water → HCID 59327647, compound

Temperature

80 °C

Methyl 2-bromo-5-fluorobenzoate (1.8 g, 7.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (2.3 g, 7.5 mmol), THF (69 mL, 850 mmol) and 2 M of sodium carbonate in water (15.0 mL, 30.0 mmol) were combined, and the mixture was degassed and flushed with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (158 mg, 225 μmol) was added, and the mixture was again degassed and flushed with nitrogen. The mixture was heated at 80° C. for 1 hour. The mixture was then cooled and the layers separated, diluted with EtOAc (50 mL), washed with saturated aqueous NaCl (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (0-50% EtOAc in hexanes). A solution of the crude material and Pearlman's Catalyst (0.1:0.4, Palladium hydroxide:carbon black, 1.1 g, 1.5 mmol) in MeOH (60.8 mL, 150 mmol) was hydrogenated at 1 atm at room temperature overnight. The mixture was then evacuated, purged with nitrogen, filtered through Celite® and concentrated to yield a colorless oil. This oil was dissolved in THF (30 mL, 400 mmol) and treated with borane-dimethyl sulfide complex (1.3 mL, 15.0 mmol) at room temperature. The mixture was heated to reflux for 5 hours. After cooling to room temperature, MeOH (20 mL) was slowly added and removed by rotary evaporation. Another 20 mL of MeOH was added and removed by rotary evaporation. The residue was then dissolved in EtOAc (100 mL) and washed with 1N HCl and sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The material was then purified by silica gel chromatography (0-50% EtOAc in hexanes) to yield the title compound (924 mg) as a colorless sticky solid.

1. customthe mixture was degassed
2. customflushed with nitrogen
3. customthe mixture was again degassed
4. customflushed with nitrogen
5. temperatureThe mixture was then cooled
6. customthe layers separated
7. additiondiluted with EtOAc (50 mL)
8. washwashed with saturated aqueous NaCl (30 mL)
9. dry with materialdried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo
12. customThe crude product was purified by flash chromatography (0-50% EtOAc in hexanes)
13. customThe mixture was then evacuated
14. custompurged with nitrogen
15. filtrationfiltered through Celite®
16. concentrationconcentrated
17. customto yield a colorless oil
18. additiontreated with borane-dimethyl sulfide complex (1.3 mL, 15.0 mmol) at room temperature
19. temperatureThe mixture was heated
20. temperatureto reflux for 5 hours
21. temperatureAfter cooling to room temperature
22. customremoved by rotary evaporation
23. additionAnother 20 mL of MeOH was added
24. customremoved by rotary evaporation
25. dissolutionThe residue was then dissolved in EtOAc (100 mL)
26. washwashed with 1N HCl and sat. NaHCO3
27. dry with materialdried over Na2SO4
28. filtrationfiltered
29. concentrationconcentrated
30. customThe material was then purified by silica gel chromatography (0-50% EtOAc in hexanes)

ORD record

ord-d1bf9616e2204ad2aeda7fd5eac7de16

Source dataset

uspto-grants-2012_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08304432B2