Potassium Phosphate, Tribasic → methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate

HRID 394718Notes

Reaction equation

HRID 394718 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[CH2:16])[CH:10]([C:17]([O:19][CH3:20])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.I[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=2)[N:34]=[CH:33][C:32]=1[F:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2].[Cl-]>[F:43][C:32]1[CH:33]=[N:34][C:35]2[C:40]([C:31]=1[CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH:10]1[C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH3:16])=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 789669-Borabicyclo(3.3.1)nonaneHCID 116666153-Fluoro-4-iodo-6-methoxy-quinolineHCID 667752561-Tert-butyl 3-methyl 4-allylpiperidine-1,3-dicarboxylate

Product 1

HCID 86586486methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylateYield 76.6%

Reagents, catalysts & solvents 2

HCID 178478644HCID 178478644, compoundCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of 1.45 g of methyl (3RS,4RS)-1-(tert-butyloxycarbonyl)-4-allylpiperidine-3-carboxylate in 20-cm3 of tetrahydrofuran was slowly added, at a temperature in the region of 0° C. with stirring and under an inert atmosphere, to 16-cm3 of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran. The mixture was then brought to a temperature in the region of 20° C. while the stirring was continued for a further 4 hours. 1.52 g of 4-iodo-3-fluoro-6-methoxyquinoline in solution in 40-cm3 of tetrahydrofuran were added, followed by 100 mg of palladiumdiphenylphosphinoferrocene chloride and finally 3.18 g of tribasic potassium phosphate. The reaction mixture was heated for 15 hours under reflux and then filtered in the hot state on sintered glass. The filtrate was taken up in 50-cm3 of ethyl acetate and concentrated to dryness under reduced pressure (5 kPa). The residue was taken up in 75-cm3 of ethyl acetate and 40-cm3 of water. The organic phase was separated after settling out, washed twice with 40-cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue was purified by chromatography, under a nitrogen pressure of 50 kPa, on a column of silica gel (particle size 20-45 μ; diameter 2.5 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (75/25 by volume) and collecting 50-cm3 fractions. Fractions 16 to 22 were combined and then concentrated. 1,77 g of methyl (3RS,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)-3-propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate were obtained in the form of a colorless oil.

Workup

  1. customwas then brought to a temperature in the region of 20° C. while the stirring
  2. temperatureThe reaction mixture was heated for 15 hours
  3. temperatureunder reflux
  4. filtrationfiltered in the hot state on sintered glass
  5. concentrationconcentrated to dryness under reduced pressure (5 kPa)
  6. customThe organic phase was separated
  7. washwashed twice with 40-cm3 of a saturated aqueous sodium chloride solution
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C
  11. customThe residue was purified by chromatography, under a nitrogen pressure of 50 kPa
  12. washon a column of silica gel (particle size 20-45 μ; diameter 2.5 cm; height 40 cm), eluting with a mixture of cyclohexane-ethyl acetate (75/25 by volume)
  13. customcollecting 50-cm3 fractions
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-1d4ece3a23214a37aff23617d63ac6fb
Source dataset
uspto-grants-2003_08
Patent number
US06602884B2

Reaction notes

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