Tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate → 1,1-Dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-hydroxypropyl)-1-piperidinecarboxylate

HRID 489789Notes

Reaction equation

HRID 489789 reaction equation
[F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[O:20]=[CH:21][CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1>O1CCCC1>[CH3:12][C:10]([CH3:11])([CH3:13])[C:9]([NH:8][C:6]1[N:7]=[C:2]([F:1])[C:3]([CH:21]([OH:20])[CH2:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:28][CH2:29]2)=[CH:4][CH:5]=1)=[O:14]

Participants

5

Reactant 3

HCID 10657745Tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylateHCID 13154251HCID 13154251, compoundHCID 178418339Butyllithium

Product 1

HCID 222626141,1-Dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-hydroxypropyl)-1-piperidinecarboxylateYield 34%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of N-(6-fluoro-2-pyridinyl)-2,2-dimethylpropanamide (Turner, James A., J. Org. Chem., 1983, 48, 3401–3408, 1.15 g, 5.87 mmol) in tetrahydrofuran (15 ml) was added dropwise a solution of n-butyllitium (8.1 ml, 12.9 mmol) at −78° C. over 10 min., and the mixture was stirred at 0° C. for 1 h. After cooling to −78° C., a solution of 1,1-dimethylethyl 4-(3-oxopropyl)-1-piperidinecarboxylate (Keenan, Richard M. et. al, J. Med. Chem., 1999, 42, 545–559, 1.70 g, 7.04 mmol) in tetrahydrofuran (5 ml) was added to the mixture. After stirring for 0.5 h, the mixture was allowed to warm up to room temperature and stirred for further 2 h. The mixture was quenched with water (20 ml) and extracted with ethyl acetate (100 ml). The organic layer was washed with brine (50 ml) and dried over magnesium sulfate. Removal of solvent gave brown oily residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1) to afford 0.86 g (34%) of the title compound as a pale yellow amorphous solid.

Workup

  1. temperatureAfter cooling to −78° C.
  2. stirringAfter stirring for 0.5 h
  3. temperatureto warm up to room temperature
  4. stirringstirred for further 2 h
  5. customThe mixture was quenched with water (20 ml)
  6. extractionextracted with ethyl acetate (100 ml)
  7. washThe organic layer was washed with brine (50 ml)
  8. dry with materialdried over magnesium sulfate
  9. customRemoval of solvent
  10. customgave brown oily residue, which
  11. customwas chromatographed on a column of silica gel eluting with ethyl acetate/hexane (2:1)

Sources & evidence

ORD record
ord-a5e925da187f48d5a661b8d266beba12
Source dataset
uspto-grants-2005_12
Patent number
US06979690B2

Reaction notes

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