Piperidin-4-ol → (3E)-6-fluoro-3-[4-{5-[(4-hydroxypiperidin-1-yl)methyl]-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one

HRID 2196167Notes

Reaction equation

HRID 2196167 reaction equation
[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3/[CH:13]=[C:14]([C:19]4[CH:20]=[C:21]([CH:24]=O)[S:22][CH:23]=4)[C:15]([CH3:18])([CH3:17])[O:16]/3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CO.O.C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:16][C:15]([CH3:18])([CH3:17])[C:14]([C:19]4[CH:20]=[C:21]([CH2:24][N:30]5[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]5)[S:22][CH:23]=4)=[CH:13]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 79341Piperidin-4-olHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 589262724-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde

Product 1

HCID 58926255(3E)-6-fluoro-3-[4-{5-[(4-hydroxypiperidin-1-yl)methyl]-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde (120 mg, 0.34 mmol), 4-hydroxypiperidine (69 mg, 0.68 mmol) and 100 mg of 4 Å molecular sieves in 5 mL of anhydrous DMF was stirred under nitrogen for 16 hours. Acetic acid (20 mg) and 1M sodium cyanoborohydride (0.68 mL, 0.68 mmol) were then added. The mixture was diluted with 5 mL of anhydrous methanol and stirred at room temperature for 3 hours. The mixture was poured into 100 mL of water with stirring, and basified to about pH 8 with saturated NaHCO3 solution. The resulting precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 10-20% MeOH/CHCl3 to give (3E)-6-fluoro-3-[4-{5-[(4-hydroxypiperidin-1-yl)methyl]-3-thienyl}-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as yellow powder. Yield: 38 mg, 26%.

Workup

  1. stirringstirred at room temperature for 3 hours
  2. stirringwith stirring
  3. customThe resulting precipitates
  4. filtrationwere filtered
  5. washwashed with water
  6. customdried in vacuo
  7. customto give the crude product, which
  8. customwas purified through silica gel column with 10-20% MeOH/CHCl3

Sources & evidence

ORD record
ord-6504740923e94957a8853c8b2b10580f
Source dataset
uspto-grants-2012_12
Patent number
US08338415B2

Reaction notes

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