Diethyl Ether → HCID 59134644, compound

Temperature

-78 °C

At −78° C. under Ar a dry 250 ml 3 neck flask was charged with 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (4.5 g, 0.018 mol). Dry ether (100 mL) was added and to the stirred solution, nBuLi (9.2 mL, 0.018 mol) was added dropwise via airtight syringe through a rubber septum. The resulting pale orange colored solution was stirred at −78° C. for 30 min. 5-chloropicolinenitrile (2.5 g, 0.018 mol) was then added as a thick slurry in dry ether (approx 10 mL) via wide neck funnel. The resulting solution turned dark red in color and was stirred at −78° C. for 1 hr. LCMS indicated that the reaction was complete and, at −78° C. the reaction mixture was quenched with 1.0M HCl (approx 50 mL). The cooling bath was removed and as the reaction mixture reaction reached ambient temperature, (22° C.), the organic solution turned pale green in color. The solution was transferred to a separation funnel and the organic layer separated. The aqueous phase was washed with EtOAc (20 mL) and the combined organic portions dried over anhydrous Na2SO4, decanted and concentrated yielding a pale brown oil. This was dissolved in hexane (ca 15 mL) and loaded directly onto a silica gel ISCO cartridge (330 g, previously equilibrated with hexanes) and elution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min. Elution time of the product was 17 to 20 mins and (5-chloropyridin-2-yl)(3-fluoro-5-(trifluoromethyl)phenyl)methanone (4.1 g, 75% yield) was isolated as a pale yellow oil which crystallized on standing. Rf0.74 (Hexane:EtOAc 4:1) LCMS: 2.03 min [M+1] 304.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.98 min (4 min gradient, MeOH/H2O 0.2% PPA Purity 98%; NMR: 400 MHz 1H (CDCl3) 8.69 ppm, 1H, d, J=2.64 Hz; 8.22 ppm, 1H, s; 8.13 ppm, 1H, d, J=8.36 Hz; 8.07 ppm, 1H, brd, J=8.4 Hz; 7.93 ppm, 1H, dd, J=2.2 and J=8.36 Hz; 7.57 ppm, 1H, brd, J=8.4 Hz.

1. additionwas added dropwise via airtight syringe through a rubber septum
2. stirringwas stirred at −78° C. for 1 hr
3. customwas complete and, at −78° C.
4. customwas quenched with 1.0M HCl (approx 50 mL)
5. customThe cooling bath was removed and as the reaction mixture reaction
6. customreached ambient temperature
7. custom, (22° C.),
8. customThe solution was transferred to a separation funnel
9. customthe organic layer separated
10. washThe aqueous phase was washed with EtOAc (20 mL)
11. dry with materialthe combined organic portions dried over anhydrous Na2SO4
12. customdecanted
13. concentrationconcentrated
14. customyielding a pale brown oil
15. washelution at 100 mL/min gradient 0 to 70% EtOAc in hexanes over 45 min
16. washElution time of the product
17. waitwas 17 to 20 mins

ORD record

ord-71febb0d545148d284af3ab485a46769

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07888376B2