Triethylamine → 2,4'-Bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanone

HRID 240397Notes

Reaction equation

HRID 240397 reaction equation
Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[F:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=1.CN(C(ON1N=N[C:37]2[CH:38]=[CH:39][CH:40]=[N:41][C:36]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([N:21]2[CH2:20][CH2:19][C:18]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([F:12])=[CH:26][CH:25]=3)([OH:24])[CH2:23][CH2:22]2)=[O:6])[C:2]=1[C:38]1[CH:37]=[CH:36][N:41]=[CH:40][CH:39]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 762582-Chloronicotinic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 702405494-[(4-Fluorophenyl)methyl]piperidin-4-ol hydrochloride

Product 1

HCID 715476442,4'-Bipyridin-3-yl(4-(4-fluorobenzyl)-4-hydroxypiperidin-1-yl)methanoneYield 56.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

A suspension of 2-chloronicotinic acid (0.15 g), 4-(4-fluorobenzyl)-4-hydroxypiperidine hydrochloride (0.26 g), HATU (0.43 g) and triethylamine (0.66 mL) in DMF (5 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in DME (5.0 mL), and pyridine-4-boronic acid (0.13 g), sodium carbonate (0.20 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and water (1.0 mL) were added thereto, and the mixture was stirred at 140° C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and then purified by preparative HPLC(C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.21 g).

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. washThe extract was washed with saturated brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customThe solvent was evaporated under reduced pressure
  5. dissolutionThe residue was dissolved in DME (5.0 mL)
  6. additionpyridine-4-boronic acid (0.13 g), sodium carbonate (0.20 g), tetrakis(triphenylphosphine)palladium(0) (0.055 g) and water (1.0 mL) were added
  7. stirringthe mixture was stirred at 140° C. for 1 hr under microwave irradiation
  8. additionThe reaction mixture was diluted with water
  9. extractionthe mixture was extracted with ethyl acetate
  10. washThe extract was washed with saturated brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. customThe solvent was evaporated under reduced pressure
  13. customThe residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane)
  14. custompurified by preparative HPLC(C18, mobile phase
  15. concentrationwater/acetonitrile (containing 0.1% TFA)), and the obtained fraction was concentrated under reduced pressure
  16. additionTo the residue was added saturated aqueous sodium hydrogen carbonate solution
  17. extractionthe mixture was extracted with ethyl acetate
  18. dry with materialThe extract was dried over anhydrous sodium sulfate
  19. customthe solvent was evaporated under reduced pressure

Sources & evidence

ORD record
ord-369070ca696a444dbc46d6b0ee70b171
Source dataset
uspto-grants-2014_02
Patent number
US08648079B2

Reaction notes

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