Ethanol → tert-Butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate

HRID 451559Notes

Reaction equation

HRID 451559 reaction equation
[F:1][C:2]1([F:17])[C:7](O)(O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:4]1[CH2:5][CH2:6][CH:7]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([F:17])([F:1])[CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]

Participants

6

Reactant 4

HCID 702EthanolHCID 7504Benzylamine2×HCID 4311764Sodium borohydride3×HCID 57415845tert-Butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate

Product 1

HCID 66710726tert-Butyl 4-(benzylamino)-3,3-difluoropiperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%).

Workup

  1. temperaturewas heated
  2. temperatureto reflux with dean stark apparatus for 12 hours
  3. temperatureheated
  4. temperatureto reflux with dean stark apparatus for another 12 hours
  5. distillationAbout 50 mL of toluene were distilled off
  6. stirringstirred for another hour
  7. concentrationAfter 2 hours the reaction mixture was concentrated
  8. addition2 N Na2CO3 solution was added
  9. extractionthe aqueous phase was extracted with ethyl acetate
  10. dry with materialThe combined organic layers were dried over Na2SO4
  11. customthe solvents were evaporated
  12. customThe residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-86f5a8102aec4af48c69e116baeba5f2
Source dataset
uspto-grants-2013_07
Patent number
US08486967B2

Reaction notes

Loading…