1,1'-Binaphthyl → 1-(5-Fluoroquinolin-8-yl)piperidin-4-one

HRID 2242008Notes

Reaction equation

HRID 2242008 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.O1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16]CC1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.C1(PC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:5]1[CH:4]=[CH:3][C:2]([N:20]2[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH2:19]2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2

Participants

6

Reactant 4

HCID 117891,1'-BinaphthylHCID 674351,4-Dioxa-8-azaspiro(4.5)decaneHCID 70017DiphenylphosphineHCID 145483478-Bromo-5-fluoroquinoline

Product 1

HCID 592048481-(5-Fluoroquinolin-8-yl)piperidin-4-oneYield 70%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
55 °C

Procedure

To a 5-L jacketed cylindrical reactor equipped with an impeller-style agitator, condenser, thermocouple, and vacuum/nitrogen inlet was charged 2-L, 15% toluene solution of 8-bromo-5-fluoroquinoline, 209 g of 1,4-Dioxa-8-azaspiro[4.5]decane. Meanwhile in a 500-mL Erlenmeyer flask, a suspension of 16.5 g (26.5 mmol)±-[1,1′-binaphthalene]-2,2′-diylbis[diphenyl-Phosphine, and 6.08 g (6.64 mmol) tris[μ-[(1,2-η:4,5-η)-(1E,4E)-1,5-diphenyl -1,4-pentadien-3-one]]dipalladium in 260 g of toluene was prepared. This freshly made suspension was charged into the 5-L reactor followed by a rinse of 170 g of toluene. 166 g sodium tert-butoxide was then charged into the reactor followed by a rinse with 430 g of toluene. The reactor was degassed by vacuum to less than 125 mmHg and then filled with nitrogen to atmosphere three times. The mixture was then heated to 50-60° C. and stirred for 1 h and then heat to 65-75° and stirred at this temperature for about 10 hours. The mixture was cooled to 40-50° C. and then quenched with 800 g of water. The lower aqueous layer was split off and the volume of the organic layer was reduced to about 1.5 L by vacuum distillation. To this residual was charged 2.28 kg of 20% sulfuric acid at 25-30° C. The mixture was stirred for an hour and was clarified by filtration and a bi-phase filtrate was obtained. The aqueous phase was split and retained. Toluene 870 g was added to the aqueous solution and the mixture was neutralized by slowly adding 770 g 50% sodium hydroxide solution. The lower aqueous layer was split off and extracted with 600 g of toluene. The organic layers were combined and the volume of the reaction was reduced to about 1 L by vacuum distillation. The residue was cooled to room temperature and 480 g of toluene was charged. The mixture was heated to 45-55° C. to form a clear solution, which was filtered through a celite/charcoal pad to remove palladium. The filtrate was concentrated by vacuum distillation to about 0.7 L and diluted with 620 g heptane, cooled to −15 to −5° C. to form a slurry. The solid was collected by filtration. The product was dried by air flow at room temperature. Typical yield is about 70%.

Workup

  1. customTo a 5-L jacketed cylindrical reactor equipped with an impeller-style agitator, condenser
  2. customwas prepared
  3. additionThis freshly made suspension was charged into the 5-L reactor
  4. washa rinse of 170 g of toluene
  5. addition166 g sodium tert-butoxide was then charged into the reactor
  6. washa rinse with 430 g of toluene
  7. customThe reactor was degassed by vacuum to less than 125 mmHg
  8. additionfilled with nitrogen to atmosphere three times
  9. temperatureheat to 65-75°
  10. stirringstirred at this temperature for about 10 hours
  11. temperatureThe mixture was cooled to 40-50° C.
  12. customquenched with 800 g of water
  13. customThe lower aqueous layer was split off
  14. distillationthe volume of the organic layer was reduced to about 1.5 L by vacuum distillation
  15. additionTo this residual was charged 2.28 kg of 20% sulfuric acid at 25-30° C
  16. stirringThe mixture was stirred for an hour
  17. filtrationwas clarified by filtration
  18. customa bi-phase filtrate was obtained
  19. customThe aqueous phase was split
  20. additionToluene 870 g was added to the aqueous solution
  21. additionby slowly adding 770 g 50% sodium hydroxide solution
  22. customThe lower aqueous layer was split off
  23. extractionextracted with 600 g of toluene
  24. distillationthe volume of the reaction was reduced to about 1 L by vacuum distillation
  25. temperatureThe residue was cooled to room temperature
  26. addition480 g of toluene was charged
  27. temperatureThe mixture was heated to 45-55° C.
  28. customto form a clear solution, which
  29. filtrationwas filtered through a celite/charcoal pad
  30. customto remove palladium
  31. concentrationThe filtrate was concentrated by vacuum distillation to about 0.7 L
  32. additiondiluted with 620 g heptane
  33. temperaturecooled to −15 to −5° C.
  34. customto form a slurry
  35. filtrationThe solid was collected by filtration
  36. customThe product was dried by air flow at room temperature

Sources & evidence

ORD record
ord-dee51ebe821c48868cb53ee665622080
Source dataset
uspto-grants-2010_03
Patent number
US07671056B2

Reaction notes

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