2-Fluoropyridine-3-carbaldehyde → tert-Butyl 3-[2-(2-fluoropyridin-3-yl)-2-hydroxyethyl]pyridin-4-ylcarbamate

HRID 75205Notes

Reaction equation

HRID 75205 reaction equation
[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C([Li])CCC.[F:21][C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>C1COCC1>[F:21][C:22]1[C:23]([CH:24]([OH:25])[CH2:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:26][CH:27]=[CH:28][N:29]=1

Participants

5

Reactant 3

HCID 114349442-Fluoropyridine-3-carbaldehydeHCID 15273533tert-butyl N-(3-methylpyridin-4-yl)carbamateHCID 178418339Butyllithium

Product 1

HCID 86613267tert-Butyl 3-[2-(2-fluoropyridin-3-yl)-2-hydroxyethyl]pyridin-4-ylcarbamateYield 34.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of tert-butyl (3-methylpyridin-4-yl)carbamate (1.00 g, 4.80 mmol, Intermediate D-2) in THF (50 mL) was cooled to −78° C. under an atmosphere of nitrogen. A solution of n-butyllithium (4.80 mL, 2.5 M in hexane, 12.0 mmol) was added slowly maintaining the internal temperature below −65° C. After the addition, the mixture was warmed to 0° C. for 20 minutes (orange suspension turned homogeneous). The solution was then cooled to −78° C. and 2-fluoronicotinaldehyde (0.901 g, 7.20 mol, Intermediate D-1) in THF (5 mL) was added dropwise. After 10 minutes, the dark red/brown mixture was allowed to slowly warm to 0° C. After 30 minutes, the reaction was quenched with NH4Cl/water. The mixture was further diluted with NaHCO3/water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with 75% ethyl acetate/hexane. Pure fractions were combined, concentrated and then triturated with ethyl acetate to provide the desired product as a white solid (0.55 g, 34%). 1H NMR (DMSO-d6) δ 9.09 (s, 1H), 8.23 (d, 1H), 8.09 (d, 1H), 8.02 (s, 1H), 7.85 (m, 1H), 7.67 (d, 1H), 7.29 (m, 1H), 6.32 (d, 1H), 5.03 (m, 1H), 3.00 (m, 2H), 1.47 (s, 9H). LC/MS: 334 (M+H)+.

Workup

  1. temperaturemaintaining the internal temperature below −65° C
  2. additionAfter the addition
  3. temperatureThe solution was then cooled to −78° C.
  4. temperatureto slowly warm to 0° C
  5. waitAfter 30 minutes
  6. customthe reaction was quenched with NH4Cl/water
  7. additionThe mixture was further diluted with NaHCO3/water
  8. extractionextracted three times with ethyl acetate
  9. washThe combined extracts were washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe residue was purified by chromatography on silica gel eluting with 75% ethyl acetate/hexane
  14. concentrationconcentrated
  15. customtriturated with ethyl acetate

Sources & evidence

ORD record
ord-9036e0d5088d4997bb7441bc9aec69c1
Source dataset
uspto-grants-2014_09
Patent number
US08835423B2

Reaction notes

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