2-Bromopropane → trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine

HRID 529320Notes

Reaction equation

HRID 529320 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.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]([CH3:33])[CH3:32]>C(#N)C>[CH:31]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][NH:5][C@@H:13]2[CH2:15][C@H:14]2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1)([CH3:33])[CH3:32]

Participants

5

Reactant 3

HCID 63582-BromopropaneHCID 11430Potassium CarbonateHCID 867082342,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide

Product 1

HCID 66571696trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamineYield 40.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol) in acetonitrile (10 mL) was added potassium carbonate (254 mg, 1.838 mmol) followed by 2-bromopropane (98 mg, 0.797 mmol). The reaction mixture was heated in a sealed tube at 80° C. for 4 hours. The reaction mixture was filtered and evaporated. The resulting oil was purified by preparatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. The solution was neutralized with 1 M NaOH, concentrated and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, filtered and evaporated. The oil was dissolved in 6 ml of EtOH and 3 ml of 1 M NaOH. The reaction mixture was stirred for 20 min, and then it was concentrated. The concentrated solution was then partitioned between 2 ml of water and 5 mL of EtOAc. The organic layer was separated and evaporated. The resulting oil was dissolved in 3 mL of acetonitrile. 0.5 mL of 4 M HCl in dioxane was added. 3 mL of diethylether was added and the formed solid product was filtered. trans-N-((1-Isopropylpiperidin-4-yl)methyl)-2-phenylcyclopropanamine (80 mg, 0.246 mmol, 40.1% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.40 (m, 2H), 7.13-7.28 (m, 3H), 3.43-3.63 (m, 3H), 3.21 (d, J=6.57 Hz, 2H), 3.11 (t, 2H), 3.04 (dt, J=3.98, 7.71 Hz, 1H), 2.49-2.69 (m, 1H), 2.17 (d, J=12.63 Hz, 3H), 1.56-1.86 (m, 3H), 1.34-1.48 (m, 7H); LC-MS Rt=0.42 min; MS (ESI): 273.3 [M+H]+.

Workup

  1. filtrationThe reaction mixture was filtered
  2. customevaporated
  3. customThe resulting oil was purified by preparatory HPLC (5 to 40% AcCN: H2O with 0.1% formic acid modifier)
  4. customThe fractions were collected
  5. concentrationconcentrated
  6. extractionextracted with ethyl acetate
  7. customThe organic layer was separated
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. customevaporated
  11. dissolutionThe oil was dissolved in 6 ml of EtOH
  12. concentrationit was concentrated
  13. customThe concentrated solution was then partitioned between 2 ml of water and 5 mL of EtOAc
  14. customThe organic layer was separated
  15. customevaporated
  16. dissolutionThe resulting oil was dissolved in 3 mL of acetonitrile
  17. addition0.5 mL of 4 M HCl in dioxane was added
  18. addition3 mL of diethylether was added
  19. filtrationthe formed solid product was filtered

Sources & evidence

ORD record
ord-7460d8533d1a45ee90b5ad53f37aae36
Source dataset
uspto-grants-2016_05
Patent number
US09346840B2

Reaction notes

Loading…