tert-butyl 2-bromo-4-fluoro-3-formylbenzoate

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

Procedure: A bi-phasic solution of 2-bromo-4-fluoro-3-formyl-benzoic acid tert-butyl ester (4.25 g, 14 mmol), DME (25 mL) and hydrazine hydrate (15 mL) was heated at 90° C. for 1 hour. After cooling, the products were partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a tan solid (4.1 g, 100%). LCMS (method B) RT=3.63 min, [M+CH3CN+H]+=338/340, [M−H]−=295/297. After cooling the products were partitioned between ethyl acetate and water the aqueous layer extracted with ethyl acetate the combined organic extracts dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: To a solution of 2-bromo-4-fluoro-benzoic acid tert-butyl ester (10.0 g, 36 mmol) in THF (100 mL) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M solution, 20 mL, 36 mmol) dropwise. The reaction mixture was stirred for 1.25 hours before adding DMF (10 mL) then stirred for a further 10 minutes before quenching with acetic acid (3 mL). The products were partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a yellow oil which crystallized on standing. The crude product was triturated in cyclohexane to give the title compound as a yellow solid (6.8 g, 62%). 1H NMR (CDCl3, 400 MHz) 10.38 (1H, s), 7.80-7.73 (1H, m), 7.17 (1H, t, J=9.09 Hz), 1.62 (9H, s). then stirred for a further 10 minutes before quenching with acetic acid (3 mL) The products were partitioned between ethyl acetate and water the organic layer was separated washed with brine dried (Na2SO4) filtered concentrated in vacuo to give a yellow oil which crystallized The crude product was triturated in cyclohexane