Potassium Carbonate → 4-[((2S)-2-Amino-3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)oxy]benzonitrile

HRID 500503Notes

Reaction equation

HRID 500503 reaction equation
[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C@@H:9]([NH:20]C(=O)OC(C)(C)C)[CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][CH:35]=[CH:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:20][C@@H:9]([CH2:10][N:11]1[CH2:18][CH:17]2[O:19][CH:13]([CH2:14][N:15]([CH2:31][CH2:32][N:33]3[CH:37]=[CH:36][CH:35]=[CH:34]3)[CH2:16]2)[CH2:12]1)[CH2:8][O:7][C:6]1[CH:28]=[CH:29][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 116512251-(2-Bromoethyl)pyrroleHCID 86588969tert-butyl (1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-ylmethyl)ethylcarbamate

Product 1

HCID 684557444-[((2S)-2-Amino-3-{7-[2-(1H-pyrrol-1-yl)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}propyl)oxy]benzonitrileYield 90.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of tert-butyl (1S)-2-(4-cyanophenoxy)-1-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylmethyl)ethylcarbamate (Preparation J; 100.62 mg, 0.25 mmol), 1-(2-bromoethyl)pyrrole (52.21 mg, 0.30 mmol) and TEA (37.9 mg, 0.375 mmol) in DMF (2.5 mL) was stirred at rt for 2 days and then at 50° C. for 1 day. The solvent was evaporated and the resulting residue dissolved in ethyl acetate (0.5 mL). Ethyl acetate saturated with gaseous hydrochloric acid (2 mL) was added, and the reaction mixture stirred for 1.5 h at rt. The solvent was evaporated and the resulting residue dissolved in a mixture of MeCN (2.5 mL) and H2O (0.13 mL). Potassium carbonate (100 mg, 0.72 mmol) was added, and the mixture stirred overnight at rt. The mixture was filtered and the filtrate concentrated in vacuo. The resulting crude product was dissolved in DCM (2 mL), which solution was added to a ion-exchange solid-phase extraction plug (CBA, 2 g). After 80 min, the product was eluted with DCM:MeCN (4×2 mL of 4:1), followed by DCM:MeOH:TEA (8:1:1), to give 89.7 mg (90.7%) of the title compound.

Workup

  1. waitat 50° C. for 1 day
  2. customThe solvent was evaporated
  3. dissolutionthe resulting residue dissolved in ethyl acetate (0.5 mL)
  4. additionEthyl acetate saturated with gaseous hydrochloric acid (2 mL) was added
  5. stirringthe reaction mixture stirred for 1.5 h at rt
  6. customThe solvent was evaporated
  7. dissolutionthe resulting residue dissolved in a mixture of MeCN (2.5 mL) and H2O (0.13 mL)
  8. stirringthe mixture stirred overnight at rt
  9. filtrationThe mixture was filtered
  10. concentrationthe filtrate concentrated in vacuo
  11. dissolutionThe resulting crude product was dissolved in DCM (2 mL)
  12. additionwhich solution was added to a ion-exchange solid-phase extraction plug (CBA, 2 g)
  13. waitAfter 80 min
  14. washthe product was eluted with DCM

Sources & evidence

ORD record
ord-964d2dd110d749468ae611d2417e1aa8
Source dataset
uspto-grants-2010_08
Patent number
US07772229B2

Reaction notes

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