Hydrochloric Acid → HCID 18931033, compound

To a stirred solution of (4-fluorophenyl)acetone (1.52 g, 10 mmol) in anhydrous THF (10 mL) at -78° C. under N2 was added lithium diisopropylamide mono(tetrahydrofuran) (5.33 mL of a 1.5M solution in THF, 8 mmol). The solution was allowed to warm to room temperature over 1 h, and then was cooled to -78° C. This solution was then transferred via cannula to a solution of 2-chloronicotinyl chloride (3.50 g, 20 mmol) in anhydrous THF (20 mL) at -78° C. After stirring at -78° C. for 1 h, the solution was poured into 10% NH4Cl (50 mL), and the aqueous layer extracted with ether (2×80 mL). The combined organic extracts were washed with 5% NaHCO3, dried over MgSO4, and concentrated in vacuo to a brown oil (4.75 g). Prior to the workup above, 3-(trifluoromethyl)diazonium chloride was prepared by addition of concentrated HCl (1 mL) to a suspension of 3-(trifluoromethyl)aniline (1.29 g, 8 mmol) in water (5 mL) followed by addition of acetic acid (0.5 mL for solubility) and sodium nitrite (0.55 g, 8 mmol) at 0° C. To the brown oil (4.75 g) from the reaction above dissolved in ethanol (25 mL) at 0° C. was added potassium hydroxide (1.5 g, 26.7 mmol) in water (10 mL) followed by more water (60 mL). To this solution was added the diazonium salt solution over 2 min. After 5 min, the aqueous solution was extracted with ethyl acetate (2×80 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to a brown oil. Purification by flash chromatography eluting with 15-20% ethyl acetate/hexanes afforded the title compound of Step A as a brown oil (1.27 g) which was somewhat impure by 1H NMR. 1H NMR (CDCl3, 400 MHz) δ8.35 (m, 1H), 7.90 (s,1H), 7.80 (m,2H), 7.64 (t, 1H), 7.53 (m,2H), 7.43 (m, 1H), 7.20 (m,3H), 2.15 (s,3H).

1. temperaturewas cooled to -78° C
2. extractionthe aqueous layer extracted with ether (2×80 mL)
3. washThe combined organic extracts were washed with 5% NaHCO3
4. dry with materialdried over MgSO4
5. concentrationconcentrated in vacuo to a brown oil (4.75 g)
6. waitAfter 5 min
7. extractionthe aqueous solution was extracted with ethyl acetate (2×80 mL)
8. dry with materialThe combined organic extracts were dried over MgSO4
9. concentrationconcentrated in vacuo to a brown oil
10. customPurification by flash chromatography
11. washeluting with 15-20% ethyl acetate/hexanes

ORD record

ord-d6168f9fd3de443db0d2b8b4c83899f4

Source dataset

uspto-grants-1998_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05739326