phenylmethyl (1S,4S,6S)-4-({[5-(trifluoromethyl)-2-pyridinyl]amino}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate → N-[(1S,4S,6S)-3-Azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine

HRID 1094754Notes

Reaction equation

HRID 1094754 reaction equation
[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][C@@H:11]2[CH2:17][C@H:16]3[C@H:14]([CH2:15]3)[CH2:13][N:12]2C(OCC2C=CC=CC=2)=O)=[N:7][CH:8]=1>CO.CCOC(C)=O.[Pd]>[C@H:14]12[CH2:15][C@H:16]1[CH2:17][C@@H:11]([CH2:10][NH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:29])([F:1])[F:28])=[CH:8][N:7]=1)[NH:12][CH2:13]2

Participants

5

Reactant 1

HCID 59396025phenylmethyl (1S,4S,6S)-4-({[5-(trifluoromethyl)-2-pyridinyl]amino}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate

Product 1

HCID 59396026N-[(1S,4S,6S)-3-Azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalyst2×HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

In a 250 ml hydrogenation flask phenylmethyl (1S,4S,6S)-4-({[5-(trifluoromethyl)-2-pyridinyl]amino}methyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate D11 (0.275 g) was dissolved in MeOH (20 ml) and Pd/C (0.0722 g, 0.068 mmol) was added. The resulting suspension was hydrogenated at atmospheric pressure. After 25 min UPLC (Acid GEN_QC) showed a main side product with rt=0.99, peak observed: 284 (M+1). The Pd/C was filtered on a celite pad, the solvent was removed under reduced pressure to give an off-white semisolid. This solid was dissolved in anhydrous EtOAc (20 ml) and Pd/C (0.0722 g, 0.068 mmol) was added. The suspension was hydrogenated at atmospheric pressure for 50 minutes (total time). The Pd/C was filtered on a celite pad, the solvent was removed under reduced pressure to give a yellowish solid, which was purified via Biotage SP4 (NH 25+M column; Cy/EtOAc: 1/0 to 75/25 15 CV, 75/25 3 CV, to 0/1 20 CV) to give the title compound D12 (0.100 g). HPLC (walk-up): rt=3.19 min MS: (ES/+) m/z: 272 (M+1). C13H16F3N3 requires 271. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22-8.32 (m, 1 H), 7.57-7.64 (m, 1 H), 7.21-7.28 (m, 1 H), 6.60 (d, 1 H), 3.12-3.26 (m, 1 H), 2.89-3.10 (m, 3 H), 2.37-2.47 (m, 1 H), 1.83-1.94 (m, 1 H), 1.05-1.18 (m, 1 H), 0.69-0.98 (m, 2 H), 0.42-0.52 (m, 1 H), 0.28-0.39 (m, 1 H).

Workup

  1. customwith rt
  2. filtrationThe Pd/C was filtered on a celite pad
  3. customthe solvent was removed under reduced pressure
  4. customto give an off-white semisolid
  5. waitThe suspension was hydrogenated at atmospheric pressure for 50 minutes
  6. filtrationThe Pd/C was filtered on a celite pad
  7. customthe solvent was removed under reduced pressure
  8. customto give a yellowish solid, which
  9. customwas purified via Biotage SP4 (NH 25+M column; Cy/EtOAc: 1/0 to 75/25 15 CV, 75/25 3 CV, to 0/1 20 CV)

Sources & evidence

ORD record
ord-9236e9e7efaa4f54b22c9f9e41206ec9
Source dataset
uspto-grants-2012_03
Patent number
US08133908B2

Reaction notes

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