Diisopropylethylamine → (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile

HRID 2109489Notes

Reaction equation

HRID 2109489 reaction equation
[NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]([N:32]1[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]1[C:38]#[N:39])=[O:31]>C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[O:12][C:10]([C:5]12[CH2:6][CH2:7][C:2]([NH:1][CH2:29][C:30]([N:32]3[CH2:36][C@@H:35]([F:37])[CH2:34][C@H:33]3[C:38]#[N:39])=[O:31])([CH2:9][CH2:8]1)[CH2:3][CH2:4]2)=[O:11]

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 21090395(2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrileHCID 231496982-Tetrahydropyranyl 4-aminobicyclo[2,2,2]octane-1-carboxylate

Product 1

HCID 59383132(2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrileYield 79.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

2-Tetrahydropyranyl 4-aminobicyclo[2,2,2]octane-1-carboxylate (62.9 mg) was suspended in acetonitrile (1 mL). To this suspension, diisopropylethylamine (47 μL) was added. With the solution chilled in an ice bath, (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (53.1 mg) in acetonitrile (0.8 mL) was added and the mixture was stirred for 4 hours. Subsequently, the reaction mixture was concentrated, and ethyl acetate and water were added to dissolve the residue. To this solution, an aqueous sodium bicarbonate solution was added to make the solution basic and the solution was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=10:1) to obtain (2S,4S)-1-[[N-[4-(2-tetrahydropyranyl)oxycarbonylbicyclo[2,2,2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (73.3 mg).

Workup

  1. temperatureWith the solution chilled in an ice bath
  2. concentrationSubsequently, the reaction mixture was concentrated
  3. additionethyl acetate and water were added
  4. dissolutionto dissolve the residue
  5. additionTo this solution, an aqueous sodium bicarbonate solution was added
  6. extractionthe solution was extracted with ethyl acetate
  7. washThe ethyl acetate layer was washed with saturated brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe resulting residue was purified by silica gel column chromatography (eluant: dichloromethane: methanol=10:1)

Sources & evidence

ORD record
ord-de444184e7f946ecb15bbd9aa35be9ea
Source dataset
uspto-grants-2009_04
Patent number
US07514571B2

Reaction notes

Loading…