1,2-Dichloroethane → 1,1-Dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

HRID 2098449Notes

Reaction equation

HRID 2098449 reaction equation
[C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:29][C:30]([CH3:47])([CH3:46])[C@@H:31]([C:43](O)=[O:44])[NH:32]C(OCC1C=CC=CC=1)=O.CN1CCOCC1.C([O-])=O.[NH4+]>C(Cl)Cl.O.C([O-])([O-])=O.[Na+].[Na+].[Pd].C(O)C>[CH3:29][C:30]([CH3:47])([CH3:46])[C@@H:31]([C:43]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:44])[NH2:32]

Participants

12

Reactant 6

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 757711-HydroxybenzotriazoleHCID 2723923Ammonium formateHCID 9899995(2S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acidHCID 11521263(1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane

Product 1

HCID 582864131,1-Dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateYield 95.3%

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 10340Sodium CarbonateSolvent

Procedure

To a solution of 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.25 g, 57.6 mmol) in CH2Cl2 (567 mL) was added EDC (40.8 g, 213 mmol), HOBt (10.86 g, 70.9 mmol), 3-methyl-N-{[(phenylmethyl)oxy]carbonyl}-L-valine (18.82 g, 70.9 mmol), and NMM (37.4 g, 340 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with water (75 ml) and sat. Na2CO3 (75 ml). Stirring was continued for an additional 0.5 h then the two layers were separated. The organic solution was washed with sat. NaHCO3, 1N HCl, sat. NaHCO3, and brine. The organic layer was passed over a phase separator and concentrated under reduced pressure. To the residue was added ethanol (567 ml), 10% Pd/C (6.04 g) and ammonium formate (35.8 g, 567 mmol). The solution was stirred at room temperature for 18 h and then filtered over a pad of celite. The resulting solution was concentrated to afford an off white residue. The residue was dissolved in CH2Cl2 and washed with sat. Na2CO3. The layers were separated and the aqueous layer was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were passed over a phase separator and concentrated to afford the desired product (17.1 g, 54.9 mmol) as an off white residue. LCMS (m/z): 312.2 (M+H).

Workup

  1. stirringStirring
  2. waitwas continued for an additional 0.5 h
  3. customthe two layers were separated
  4. washThe organic solution was washed with sat. NaHCO3, 1N HCl, sat. NaHCO3, and brine
  5. concentrationconcentrated under reduced pressure
  6. stirringThe solution was stirred at room temperature for 18 h
  7. filtrationfiltered over a pad of celite
  8. concentrationThe resulting solution was concentrated
  9. customto afford an off white residue
  10. washwashed with sat. Na2CO3
  11. customThe layers were separated
  12. extractionthe aqueous layer was extracted three times with CH2Cl2
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-13fbae2a9ed24722ac1de074796c1542
Source dataset
uspto-grants-2013_05
Patent number
US08450484B2

Reaction notes

Loading…