Diisopropylamine → 2-(4-t-Butoxy-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde

To a solution of LDA (1.20 mmol, prepared from diisopropylamine (0.16 mL) and n-BuLi (2.5M in hexanes, 0.48 mL) in THF (2.0 mL) at 0° C. was added N-(2-cyclopropyl-ethylidene)cyclohexylamine (1.24 mmol, from step 3a) dropwise, and the reaction mixture was warmed to room temperature and stirred for 15 minutes. To this solution was added 4-t-butoxy-5-fluoro-3-methylpyridine (0.10 mL, 0.50 mmol) in THF (0.5 mL) dropwise and the mixture was stirred for 3.5 hours. The reaction was then quenched with acetic acid (1M, 3 mL), diluted with hexanes (20 mL) and dilute acetic acid (1M, 20 mL), and stirred vigorously for 1 hour. The organic layer was separated, washed with water, saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel, eluting with 5% to 15% ethyl acetate in hexanes, to afford the title compound (0.098 g, 75% yield) as an oil. MS 266 (M+H)+ ; 1H NMR (CDCl3) δ0.19-0.32 (m, 2H), 0.52-0.75 (m, 2H), 1.42 (d, 9H, J=1.1 Hz), 1.42-1.60 (m, 1H), 2.20 (s, 3H), 3.16 (dd, 1H, J=2.6 Hz, J =8.8 Hz), 8.29 (d, 1H, J=2.2 Hz), 9.86 (d, 1H, J=2.6 Hz).

1. stirringthe mixture was stirred for 3.5 hours
2. customThe reaction was then quenched with acetic acid (1M, 3 mL)
3. additiondiluted with hexanes (20 mL) and dilute acetic acid (1M, 20 mL)
4. stirringstirred vigorously for 1 hour
5. customThe organic layer was separated
6. washwashed with water, saturated NaHCO3 and brine
7. dry with materialdried (MgSO4)
8. concentrationconcentrated
9. customThe residue was purified by chromatography on silica gel
10. washeluting with 5% to 15% ethyl acetate in hexanes

ORD record

ord-fd757266bda74c85b30563474045fe80

Source dataset

uspto-grants-1998_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05789591