Trifluoroacetic acid → (3R,4S)-N-Cyclopropyl-3-fluoro-1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine

HRID 1409745Notes

Reaction equation

HRID 1409745 reaction equation
[CH:1]1([N:4]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.C(N)(OC(C)(C)C)=O.FC(F)(F)C(O)=O>CN(C)C=O.ClCCl.CCN(CC)CC>[CH:1]1([NH:4][C@H:12]2[CH2:17][CH2:16][N:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=3)[CH2:14][C@H:13]2[F:18])[CH2:2][CH2:3]1

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 77922tert-Butyl carbamateHCID 923422-Chloro-5-(trifluoromethyl)pyridineHCID 68289942tert-butyl N-cyclopropyl-N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate

Product 1

HCID 68351864(3R,4S)-N-Cyclopropyl-3-fluoro-1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Procedure

A solution of tert-butyl N-cyclopropyl-N-[(3R,4S)-3-fluoropiperidin-4-yl]carbamate (100 mg), 2-chloro-5-trifluoromethylpyridine (141 mg) and Et3N (78 mg) in N,N-dimethylformamide (2 mL) is heated in a microwave reactor at 130° C. for 3 h. After concentration the residue is purified by chromatography on silica gel eluting with 0% to 30% ethyl acetate/hexane to give the intermediate product [LC (method 20): tR=3.19 min; mass spectrum (APCI): m/z=404 [M+H]+]. The Boc-amine is dissolved in dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) is added and the solution is stirred at r.t. for 1 h. After concentration dichloromethane (3 mL) and 2 M NaOH (2 mL) are added and the organic layer is separated, dried over MgSO4 and concentrated to give the title compound. LC (method 20): tR=1.99 min; Mass spectrum (APCI): m/z=304 [M+H]+.

Workup

  1. concentrationAfter concentration the residue
  2. customis purified by chromatography on silica gel eluting with 0% to 30% ethyl acetate/hexane
  3. customto give the intermediate product [LC (method 20): tR=3.19 min; mass spectrum (APCI): m/z=404 [M+H]+]
  4. concentrationAfter concentration dichloromethane (3 mL) and 2 M NaOH (2 mL)
  5. additionare added
  6. customthe organic layer is separated
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-653083ed4c7348c4912767f381bbe50c
Source dataset
uspto-grants-2014_12
Patent number
US08921398B2

Reaction notes

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