Methyl iodide → 2-Chloro-4-fluoro-3-methylbenzonitrile

Temperature

-65 °C

Stir the lithium diisopropylamide (LDA) solution for 1 h at 0° C. and then transfer it via canula, over 1 h, to a −78° C. solution of 2-chloro-4-fluoro-benzonitrile (68.7 g, 0.442 mol) in THF (1 L). Allow the temperature of the reaction mixture to warm to about −65° C. during the initial addition of the LDA solution; however, keep the internal temperature below −70° C. during the remainder of the LDA addition. Keep the temperature of the resulting dark red-orange reaction mixture below −70° C. for 5 h and add iodomethane (251.2 g, 1.77 mol, 3 mL/min) at such a rate that the reaction temperature is maintained below −65° C. during the addition. Allow the reaction mixture to slowly warm overnight. After stirring for 14 h, the temperature of the reaction mixture is −5° C. Quench the reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL) and dilute with diethyl ether (about 2 L). Separate the layers and extract the aqueous layer with diethyl ether (about 1 L). Dry the combined organic layer (about 5.5 L) over MgSO4, filter, and concentrate to afford the crude title compound as a red-brown oily solid (about 86.7 g). Subject the crude residue (dry loaded on silica gel using methylene chloride) to flash chromatography (silica gel (10×30 cm), gradient of 99:1 to 93:7 hexane/EtOAc) to obtain the title compound (56.7 g, 76%) as a white solid. m.p. 63-65° C.; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J=8.6, 5.6 Hz, 1H), 7.08 (dd, J=8.6, 8.6 Hz, 1H), 2.36 (d, J=2.4 Hz, 3H).

1. customto a −78° C.
2. customthe internal temperature below −70° C.
3. customthe temperature of the resulting dark red-orange reaction mixture below −70° C.
4. customfor 5 h
5. temperatureis maintained below −65° C. during the addition
6. customto slowly warm overnight
7. customis −5° C
8. customQuench
9. customthe reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL)
10. customSeparate the layers
11. extractionextract the aqueous layer with diethyl ether (about 1 L)
12. dry with materialDry the combined organic layer (about 5.5 L) over MgSO4
13. filtrationfilter
14. concentrationconcentrate
15. customto afford the crude title compound as a red-brown oily solid (about 86.7 g)

ORD record

ord-fafba4a53e09425ba9c1fa2bd439ce15

Source dataset

uspto-grants-2010_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07807691B2