Trifluoroacetic acid → tert-butyl (2R)-1-(3-cyano-3-fluoropyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

HRID 1898509Notes

Reaction equation

HRID 1898509 reaction equation
[C:1]([C:3]1([F:15])[CH2:7][CH2:6][N:5]([C:8]([O:10]C(C)(C)C)=O)[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.[C:23]([O:27][C:28]([NH:30][C@H:31]([C:35]([CH3:38])([CH3:37])[CH3:36])C(O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1([F:15])[CH2:7][CH2:6][N:5]([C:8](=[O:10])[C@H:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:4]1)#[N:2]

Participants

9

Reactant 6

HCID 6422Trifluoroacetic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 7005057(2R)-2-{[(tert-butoxy)carbonyl]amino}-3,3-dimethylbutanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57516605Tert-butyl 3-cyano-3-fluoropyrrolidine-1-carboxylate

Product 1

HCID 86657871tert-butyl (2R)-1-(3-cyano-3-fluoropyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamateYield 83%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a solution of tert-butyl 3-cyano-3-fluoropyrrolidine-1-carboxylate (240 mg, 1.12 mmol) in CH2Cl2 (5 mL) was added TFA (2.0 mL, 26.0 mmol). The pale yellow reaction mixture was stirred at room temperature for 4 h then concentrated to a yellow oil and dried under high vacuum. In a 50 mL flask were combined the above oil (237 mg, 1.04 mmol), (R)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (200 mg, 0.87 mmol), and HOBT (146 mg, 0.95 mmol). Then added DMF (4 mL) followed by HATU (362 mg, 0.95 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.59 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×) then dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (20% to 50% EtOAc/hexanes) to isolate 234 mg (83%) of tert-butyl (2R)-1-(3-cyano-3-fluoropyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate as a viscous colorless oil.

Workup

  1. concentrationthen concentrated to a yellow oil
  2. customdried under high vacuum
  3. customIn a 50 mL flask were combined
  4. stirringThe yellow reaction mixture was stirred at room temperature overnight
  5. customthen quenched with H2O
  6. extractionextracted with EtOAc (3×)
  7. washThe combined organics were washed with H2O (3×)
  8. dry with materialthen dried over MgSO4
  9. concentrationconcentrated
  10. customThe crude residue was purified by SiO2 chromatography (20% to 50% EtOAc/hexanes)

Sources & evidence

ORD record
ord-98e02b84bfc140dda2004cea1ef7358a
Source dataset
uspto-grants-2013_08
Patent number
US08518945B2

Reaction notes

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