Formaldehyde → (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)pyrrolidin-2-one

HRID 1374288Notes

Reaction equation

HRID 1374288 reaction equation
[CH:1]([N:4]([CH3:31])[C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[C:12]2=[O:27])[C@H:7]([CH2:28][CH2:29][CH3:30])[CH2:6]1)([CH3:3])[CH3:2].Br.CC(O)=O.CCOCC.O.C=O>CCOC(C)=O>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([C@H:8]2[CH2:9][CH2:10][C@@H:5]([N:4]([CH:1]([CH3:2])[CH3:3])[CH3:31])[CH2:6][C@H:7]2[CH2:28][CH2:29][CH3:30])[C:12]1=[O:27]

Participants

6

Reactant 4

HCID 712FormaldehydeHCID 21584184Diethylether waterHCID 21893785Acetic Acid Mixture with Hydrobromic AcidHCID 86596858benzyl (S)-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate

Product 1

HCID 68767742(S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl)pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

The entirety of benzyl (S)-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]-2-oxopyrrolidin-3-ylcarbamate prepared in Step 2 (assumed 8.2 mmol) was wet with 3 mL of EtOAc and then charged with 30% HBr/AcOH (30 mL). The reaction vessel warms and a vigorous gas evolution occurs. The mixture was stirred for 25 min at RT and then the flask was placed in a cool water bath before the addition of 150 mL of 1:1 Et2O/H2O. This mixture was mixed and separated, and the aqueous phase was extracted once with Et2O. The aqueous phase was basified to pH 14 through the addition of solid NaOH (the temperature of this exothermic process was controlled through the intermittent use of an external ice bath) and the resulting mixture was extracted with EtOAc (75 mL, then 2×35 mL). The organic extracts were combined, washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give an orange oil, contaminated with some powdery white solid (presumed to be formaldehyde-related). The mixture was dissolved in a minimal volume of EtOAc, filtered, and concentrated to provide (S)-3-amino-1-[(1S,2R,4R)-4-(isopropyl(methyl)amino)-2-propylcyclohexyl]pyrrolidin-2-one (2.31 g; 1H-NMR shows ˜30% EtOAc, indicating an estimated 7.0 mmol of product from Steps 1–3). MS found: (M+H)+=296.6.

Workup

  1. additionThis mixture was mixed
  2. customseparated
  3. extractionthe aqueous phase was extracted once with Et2O
  4. additionThe aqueous phase was basified to pH 14 through the addition of solid NaOH (the temperature of this exothermic process
  5. customwas controlled through the intermittent use of an external ice bath
  6. extraction) and the resulting mixture was extracted with EtOAc (75 mL
  7. washwashed with brine (30 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto give an orange oil
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-c8a204e0b0f54a6fbd58df2092cd38e9
Source dataset
uspto-grants-2007_01
Patent number
US07163937B2

Reaction notes

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