Phenyl isocyanate → N-phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide

HRID 529297Notes

Reaction equation

HRID 529297 reaction equation
FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:25]=[O:26].[NH4+].[Cl-]>C(Cl)(Cl)Cl>[C:27]1([NH:24][C:25]([N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]3[CH2:15][C@H:14]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1

Participants

5

Reactant 3

HCID 7672Phenyl isocyanateHCID 25517Ammonium ChlorideHCID 867082342,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

Product 1

HCID 66571584N-phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamideYield 80%

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (60 mg, 0.184 mmol) (Example 11b) in chloroform (2 mL) was added isocyanatobenzene (0.030 mL, 0.276 mmol) The reaction mixture was stirred at room temperature for 1 hr. The saturated solution of NH4Cl was added, and layers were separated. The organic layer was evaporated and the oil dissolved in ethanol (2 mL) and 0.5 mL of 1 M NaOH was added. The reaction mixture was stirred for 1 hour at room temperature and then it was evaporated. The oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. N-phenyl-4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxamide (54 mg, 0.147 mmol, 80% yield) was isolated as yellow oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.32-7.38 (m, 2H), 7.20-7.31 (m, 4H), 7.10-7.17 (m, 1H), 7.05-7.10 (m, 2H), 6.98-7.05 (m, 1H), 4.20 (d, J=12.63 Hz, 2H), 2.79-3.01 (m, 2H), 2.65 (d, J=6.57 Hz, 2H), 2.28-2.45 (m, 1H), 1.95 (ddd, J=3.16, 5.94, 9.35 Hz, 1H), 1.70-1.90 (m, 3H), 1.14-1.31 (m, 2H), 1.10 (dt, J=4.86, 9.47 Hz, 1H), 1.03 (dt, 1H); LC-MS Rt=0.56 min; MS (ESI): 350.3 [M+H]+.

Workup

  1. customlayers were separated
  2. customThe organic layer was evaporated
  3. dissolutionthe oil dissolved in ethanol (2 mL)
  4. addition0.5 mL of 1 M NaOH was added
  5. stirringThe reaction mixture was stirred for 1 hour at room temperature
  6. customit was evaporated
  7. customThe oil was purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier)
  8. customThe fractions were collected
  9. concentrationconcentrated
  10. extractionextracted with ethyl acetate
  11. washThe organic layer was washed with brine
  12. dry with materialdried over MgSO4
  13. customevaporated

Sources & evidence

ORD record
ord-042fab4224954c77b11611f6a2a9bf37
Source dataset
uspto-grants-2016_05
Patent number
US09346840B2

Reaction notes

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