Sodium hydride → (R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide

HRID 389915Notes

Reaction equation

HRID 389915 reaction equation
[Br-:1].O[CH:3]1[CH2:7][CH2:6][N@@+:5]([CH3:18])([CH2:8][C:9](=O)[NH:10][C:11]2[CH:16]=[N:15][CH:14]=CN=2)[CH2:4]1.[H-].[Na+].[CH:21]1([C:27]([OH:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1N=C[N:40]([C:43](N2C=NC=C2)=[O:44])C=1.[Na].[Br-].O[C@@H]1CC[N+](C)(CC(=O)NC2C=NC=CN=2)C1>CN(C=O)C>[Br-:1].[CH:31]1([C:27]([OH:37])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]([O:30][CH:4]2[CH2:3][CH2:7][CH2:6][N+:5]2([CH3:18])[CH:8]([C:9]2[CH:14]=[N:15][CH:16]=[CH:11][N:10]=2)[C:43](=[O:44])[NH2:40])=[O:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1

Participants

8

Reactant 6

HCID 24758Sodium hydrideHCID 682631,1'-Carbonyldiimidazole2×HCID 97700(+-)-Cyclohexylphenylglycolic acidHCID 5360545SodiumHCID 87282151(1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromideHCID 87282153(R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide2×

Product 1

HCID 131730243(R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
40 °C

Procedure

To a solution comprising (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Intermediate B) (0.317 g, 1.0 mmol) in DMF (3 ml) is added sodium hydride (0.08 g, of a 60% dispersion in oil, 2.0 mmol) in one portion. The suspension is stirred at 40° C. for 30 minutes and gas evolution is observed. Meanwhile, in a second reaction vessel, a solution of cyclohexyl-hydroxy-phenyl-acetic acid in DMF (3 ml) is treated with CDI (0.168 g, 1 mmol) in one portion. Gas evolution is observed and the reaction mixture is stirred at room temperature for 1 hour. The resulting CDI intermediate is added to the reaction vessel containing the sodium salt of (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide and the reaction mixture is stirred at 40° C. for 1 hour. The solvent is removed in vacuo and the residue is dissolved in water (10 ml) and the solution is acidified using 5% HBr (5 ml). The resulting oil precipitate is extracted with ethyl acetate (2×30 ml) and the combined organic portions are evaporated to dryness. The crude residue is purified using C-18 reverse phase column chromatography (eluent: water/1% TFA: acetonitrile/1% TFA) to yield the titled compound.

Workup

  1. stirringthe reaction mixture is stirred at room temperature for 1 hour
  2. stirringthe reaction mixture is stirred at 40° C. for 1 hour
  3. customThe solvent is removed in vacuo
  4. dissolutionthe residue is dissolved in water (10 ml)
  5. extractionThe resulting oil precipitate is extracted with ethyl acetate (2×30 ml)
  6. customthe combined organic portions are evaporated to dryness
  7. customThe crude residue is purified

Sources & evidence

ORD record
ord-731ef787b6d94184909f3280e8deaec7
Source dataset
uspto-grants-2013_02
Patent number
US08383625B2

Reaction notes

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