Hydrochloric Acid → 4-Fluoro-2-methoxy-5-methylbenzonitrile

Temperature

160 °C

A solution of 1-bromo-4-fluoro-2-methoxy-5-methyl-benzene (5.0 g, 22.8 mmol) in DMF (100 mL, 0.2 M) was treated with CuCN (4.7 g, 52.5 mmol). Equipped with a reflux condenser, the reaction was heated to 160° C. for 20 h. After cooling to room temperature, the solution was poured into a 2 L Erlenmeyer flask. ethyl acetate (400 mL), saturated aq LiCl (100 mL), 1N HCl (100 mL), 11 g of iron (III) chloride hexahydrate, and 15 mL of concd HCl was added to the solution. This green mixture was heated at 70° C. for 2 h (or until emulsion dissipated). After cooling to room temperature, the mixture was poured into a separatory funnel and extracted with ethyl acetate (600 mL total). The combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL), and saturated aq NaCl (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting powder was dissolved in ethyl acetate (50 mL) and washed with saturated aq LiCl (3×30 mL), dried over Na2SO4, filtered, and concentrated under reduced to afford 4-fluoro-2-methoxy-5-methyl-benzonitrile (3.25 g, 86%) as a beige powder: mp 99–101° C.; Rf 0.53 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.39 (d, J=8.1 Hz, 1 H), 6.65 (d, J=11.1 Hz, 1 H), 3.89 (d, J=0.9 Hz, 3 H), 2.21 (s, 3 H); Anal. calcd for C9H8FNO: C, 65.45; H, 4.88. Found C, 65.17; H, 4.97.

1. customEquipped with a reflux condenser
2. temperatureAfter cooling to room temperature
3. additionthe solution was poured into a 2 L Erlenmeyer flask
4. temperatureThis green mixture was heated at 70° C. for 2 h (or until emulsion dissipated)
5. temperatureAfter cooling to room temperature
6. additionthe mixture was poured into a separatory funnel
7. extractionextracted with ethyl acetate (600 mL total)
8. washThe combined organics were washed with 1N HCl (200 mL), saturated aq LiCl (2×200 mL), and saturated aq NaCl (100 mL)
9. dry with materialThe organic layer was dried over Na2SO4
10. filtrationfiltered
11. concentrationconcentrated under reduced pressure
12. dissolutionThe resulting powder was dissolved in ethyl acetate (50 mL)
13. washwashed with saturated aq LiCl (3×30 mL)
14. dry with materialdried over Na2SO4
15. filtrationfiltered
16. concentrationconcentrated

ORD record

ord-9c0c9c09f629422e8a9820c9be84b55a

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07189749B2