2,2-Difluoroethanamine → N-(tert-butoxycarbonyl)piperidine

HRID 1801515Notes

Reaction equation

HRID 1801515 reaction equation
[C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)CN>ClCCCl.C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]

Participants

6

Reactant 2

HCID 1362742,2-DifluoroethanamineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylate

Product 1

HCID 7010304N-(tert-butoxycarbonyl)piperidineYield 129.1%

Reagents, catalysts & solvents 3

HCID 5049666Sodium triacetoxyborohydrideCatalystHCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 1-Boc-4-piperidone (0.300 g, 1 eq) and 2,2-difluoroethylamine (0.244 g, 2 eq) in 1,2-dichloroethane (6 mL) is added NaBH(OAc)3 (0.640 mg, 2 eq). After 18 h, the solution is diluted with CH2Cl2, washed with NaHCO3 (sat.), brine, dried over Na2SO4 and concentrated. The resulting residue is purified by flash chromatography Hex/EtOAc (1:1) to give the corresponding N-Boc piperidine (0.360 g, 90%). The obtained N-Boc piperidine (29 mg, 1.5 eq) is dissolved in a solution HCl in dioxane (4 M, 0.5 mL) and stirred during 30 min at RT. The solution is concentrated, the resulting residue is dissolved in DMSO (0.5 mL), Et3N (40 μL, 4 eq) is added followed by 50d (35 mg, 1 eq). The solution is heated at 50° C. for 1 h and ammonium acetate (500 mg) is added and the heating is pursued at 140° C. during 4 h. The solution is diluted with H2O/AcOH and purified by prep HPLC to give 5004 (10 mg, 24%).

Workup

  1. washwashed with NaHCO3 (sat.), brine
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated
  4. customThe resulting residue is purified by flash chromatography Hex/EtOAc (1:1)

Sources & evidence

ORD record
ord-822f8420db134c7aaaa4fc0e59de90db
Source dataset
uspto-grants-2013_01
Patent number
US08349839B2

Reaction notes

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