1,2-Dichloroethane → tert-Butyl 6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate

HRID 455285Notes

Reaction equation

HRID 455285 reaction equation
[CH:1]12[CH:6]([C:7](OCC)=[O:8])[CH:5]1[CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]2.[Li+].[OH-].CC[N:23](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>C1COCC1.CO.O.CN(C=O)C>[C:7]([CH:6]1[CH:5]2[CH:1]1[CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]2)(=[O:8])[NH2:23]

Participants

11

Reactant 6

HCID 111,2-DichloroethaneHCID 3939Lithium HydroxideHCID 25517Ammonium ChlorideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 235533633-Tert-butyl 6-ethyl 3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate

Product 1

HCID 70222027tert-Butyl 6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylateYield 31%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1 (6.65 g, 26.2 mmol) in THF (100 mL) and MeOH (40 mL) was added a solution of LiOH (4.40 g, 104 mmol) in H2O (40 mL) and stirred for 2 h. The reaction was quenched upon addition of 0.5 N HCl (150 mL) and extracted with EtOAc (2×200 ml). The combined organic extracts were dried over MgSO4 and concentrated under vacuum to afford the intermediate acid. Dissolved in DMF (90 mL), added DIPEA (18.8 mL, 104 mmol), EDC (5.84 g, 31.4 mmol), HOBt (4.24 g, 31.4 mmol) and NH4Cl (4.16 g, 78.5 mmol). The reaction was sealed and stirred for 48 h. Diluted the reaction with water (350 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (2×300 mL), brine (300 mL), dried over MgSO4 and concentrated under vacuum to afford 2 (1.84 g, 31%) as a white solid; 1H-nmr (400 MHz, CDCl3) δ 5.75 (s, 1H), 5.45 (s, 1H), 3.68 (d, J=7.0 Hz, 1H), 3.58 (d, J=11.0 Hz, 1H), 3.43 (d, J=11.0 Hz, 2H), 2.07 (s, 2H), 1.44 (s, 9H), 1.31-1.26 (m, 1H); LC-MS (214 nM) 2.15 min (>98%), m/z 171 [M-tBu].

Workup

  1. customThe reaction was quenched upon addition of 0.5 N HCl (150 mL)
  2. extractionextracted with EtOAc (2×200 ml)
  3. dry with materialThe combined organic extracts were dried over MgSO4
  4. concentrationconcentrated under vacuum
  5. customto afford the intermediate acid
  6. customThe reaction was sealed
  7. stirringstirred for 48 h
  8. additionDiluted
  9. extractionextracted with EtOAc (2×250 mL)
  10. washThe combined organic extracts were washed with water (2×300 mL), brine (300 mL)
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-a8cafb4f00bb49a6b47afd19832a66de
Source dataset
uspto-grants-2013_07
Patent number
US08497289B2

Reaction notes

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