Benzylamine → Tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylate

HRID 339703

Reaction equation

HRID 339703 reaction equation
[BH4-].[Na+].C(C(CCCC)C(O)=O)C.[F:13][CH:14]1[C:19](O)(O)[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[H-]>ClCCCl.O>[CH2:29]([NH:36][CH:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15][CH:14]1[F:13])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1

Participants

8

Reactant 5

HCID 7504BenzylamineHCID 86972-Ethylhexanoic AcidHCID 166653HydrideHCID 4311764Sodium borohydrideHCID 66790111Tert-butyl 3-fluoro-4,4-dihydroxypiperidine-1-carboxylate

Product 1

HCID 21948938Tert-butyl 4-(benzylamino)-3-fluoropiperidine-1-carboxylateYield 80%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 962WaterSolvent

Procedure

To a slurry of NaBH4 (7.567 g, 200.0 mmol) in DCE (200 mL) was added 2-Ethylhexanoic acid (95.50 mL, 600.0 mmol) slowly over 30 minutes via addition funnel. The mixture was stirred at ambient temperature for 4 hours with venting to release H2. In a separate 1 L flask was added the product from Step B (23.53 g, 100 mmol), benzylamine (16.37 mL, 150.0 mmol) and DCE (400 mL). The hydride solution was then added via addition funnel to the mixture over 1 hours while cooling the reaction in a water bath. The reaction was stirred at ambient temperature for 2 days, then diluted with water (100 mL) and concentrated in vacuo to remove solvent. The residue was partitioned between EtOAc (300 mL) and a saturated aqueous Na2CO3 solution (2×75 mL). The mixture was shaken, the layers separated and the organic phase washed again with a saturated aqueous Na2CO3 solution (100 mL) and finally with brine (50 mL). The aqueous phases were extracted with CHCl3 (3×75 mL), and the organic phases were dried over Na2CO3, filtered and concentrated. The crude product was purified by column chromatography (EtOAc/Hexane) providing 19.55 g of the pure cis product and 5.0 g of a cis/trans mixture (80%).

Workup

  1. additionvia addition funnel
  2. temperaturewhile cooling
  3. customthe reaction in a water bath
  4. stirringThe reaction was stirred at ambient temperature for 2 days
  5. concentrationconcentrated in vacuo
  6. customto remove solvent
  7. customThe residue was partitioned between EtOAc (300 mL)
  8. stirringThe mixture was shaken
  9. customthe layers separated
  10. washthe organic phase washed again with a saturated aqueous Na2CO3 solution (100 mL) and finally with brine (50 mL)
  11. extractionThe aqueous phases were extracted with CHCl3 (3×75 mL)
  12. dry with materialthe organic phases were dried over Na2CO3
  13. filtrationfiltered
  14. concentrationconcentrated
  15. customThe crude product was purified by column chromatography (EtOAc/Hexane)

Sources & evidence

ORD record
ord-8a17c3b99b9e45aea669c96d610d2bc3
Source dataset
uspto-grants-2014_11
Patent number
US08895550B2

Linked notes

Loading…