Chlorotrimethylsilane → 1-(5-Chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine

Temperature

-78 °C

A dry 250 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.5 g, 10.3 mmoles) was added to the flask and dissolved in anhydrous ether (100 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge 1½ PrecisionGlide® needle. The stirring solution was cooled to −78° C. for 10 minutes, n-BuLi (1.6M in hexanes, 6.4 mL. 10.3 mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2-cyanopyridine (1.42 g, 10.3 mmoles) in anhydrous THF (10 mL) was added from a syringe. The reaction was stirred for 2 hours at −78° C. and trimethylchlorosilane (1.41 mL, 10.3 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to −78° C., Benzylmagnesium chloride (2.0M in THF, 5.15 mL, 10.3 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 2 h. The reaction was quenched with H2O (10 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The light brown solution was washed with saturated aqueous NH4Cl (3×100 mL), then with water (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel ISCO with 95-75% hexanes in ethylacetate to yield 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 994 mg (24% yield). LC-MS (methanol) [M+1]=394. 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (1H, d, J=2.75 Hz), 7.57-7.64 (2H, m), 7.45 (2H, d, J=8.25 Hz), 7.09 -7.24 (4H, m), 6.81 (2H, d, J=6.60 Hz), 3.93 (1H, d, J=13.20 Hz), 3.46 (1H, d, J=13.20 Hz), 1.87 (2H, broad s).

1. customA dry 250 mL round bottomed flask was equipped a stirring bar
2. customfitted to an adapter
3. customThe flask was dried under vacuum
4. custompurged several times with nitrogen
5. customThe flask was fitted with a septum which
6. customThe reaction vessel was removed from the acetone/dry ice bath
7. temperatureto warm up to room temperature
8. waitAfter 30 minutes
9. temperaturethe reaction vessel was cooled to −78° C.
10. temperatureto slowly warm to room temperature for 2 h
11. customThe reaction was quenched with H2O (10 mL)
12. additionThe crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel
13. washThe light brown solution was washed with saturated aqueous NH4Cl (3×100 mL)
14. dry with materialThe organic layer was dried over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. customThe crude residue was purified by column chromatography on silica gel ISCO with 95-75% hexanes in ethylacetate

ORD record

ord-80c74a34716f48cb9d927237346b6cf9

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07652023B2