2-chloro-4-fluoro-5-methylbenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution (25 mL) of 2-chloro-4-fluoro-5-methylbenzonitrile (848 mg) in dimethyl sulfoxide were added 0.9M-dimethyl sulfoxide solution (5.56 mL) of (2S,3S)-3-hydroxy-2-methylpyrrolidine and lithium carbonate (370 mg), and the mixture was stirred at 100° C. for 1 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound as a colorless solid (yield: 374 mg). the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous sodium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) crystallized from ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using 2-chloro-4-fluoro-5-methylbenzonitrile (848 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (1.04 g) and lithium carbonate (784 mg, 10.6 mmol), the title compound was obtained as a colorless solid (yield: 590 mg) by an operation similar to that in Example 3.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, to a solution (20 mL) of 1-bromo-2-chloro-4-fluoro-5-methylbenzene (4.47 g) in N,N-dimethylformamide were added tetrakis(triphenylphosphine)palladium(0) (0.78 g) and zinc cyanide (1.23 g). The mixture was stirred at 110° C. for 13 hr and partitioned between ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) and crystallized from ethyl acetate-hexane to give the title compound as a colorless solid (yield: 2.3 g). partitioned between ethyl acetate-water The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate concentrated The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate) crystallized from ethyl acetate-hexane