Diisopropylamine → (4-tert-Butoxy-5-fluoro-3-methoxypyridin-2-yl)cyclopropylacetonitrile

HRID 983400Notes

Reaction equation

HRID 983400 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14]1.[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26](F)[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]1[C:29]([F:30])=[CH:28][N:27]=[C:26]([CH:16]([CH:13]2[CH2:15][CH2:14]2)[C:17]#[N:18])[C:25]=1[O:32][CH3:33])([CH3:22])([CH3:21])[CH3:20]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 643447CyclopropylacetonitrileHCID 225603574-tert-Butoxy-2,5-difluoro-3-methoxypyridineHCID 178418339Butyllithium

Product 1

HCID 10707715(4-tert-Butoxy-5-fluoro-3-methoxypyridin-2-yl)cyclopropylacetonitrileYield 92.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A −78° C. solution of diisopropylamine (1.3 mL, 9.0 mmol), under a nitrogen atmosphere in dry tetrahydrofuran (20 mL), was treated dropwise with 2.5 N n-butyllithium (3.6 mL, 9.0 mmol) and stirred for 10 minutes. The solution was treated dropwise with cyclopropylacetonitrile (0.8 g, 3.5 mmol) and stirred at −78° C. for 15 minutes. A solution of 4-tert-butoxy-2,5-difluoro-3-methoxypyridine (0.8 g, 3.5 mmol)[Example 7] in dry tetrahydrofuran (5 mL) was added and stirred for 1 hour at −78° C. followed by 1 hour at 0° C. The mixture was quenched with saturated ammonium chloride and extracted with diethylether. The combined extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.98 (s, 3H), 3.77 (d, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.62-0.54 (m, 2H), 0.50-0.42 (m, 1H), 0.35-0.30 (m, 1H). MSCI: m/z=279 (MH+).

Workup

  1. stirringstirred at −78° C. for 15 minutes
  2. stirringstirred for 1 hour at −78° C.
  3. waitfollowed by 1 hour at 0° C
  4. customThe mixture was quenched with saturated ammonium chloride
  5. extractionextracted with diethylether
  6. washThe combined extracts were washed with brine
  7. dry with materialdried over sodium sulfate
  8. customthe solvent removed in vacuo
  9. customThe residue was purified by column chromatography
  10. washeluting with ethyl acetate/hexanes (1:4)

Sources & evidence

ORD record
ord-0862c8180a6f4828988305354107c07b
Source dataset
uspto-grants-2005_03
Patent number
US06864259B2

Reaction notes

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