Dimethylformamide → (R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide

HRID 1690647Notes

Reaction equation

HRID 1690647 reaction equation
[Br-:1].[OH:2][CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N+:5]1([CH2:10][C:11](=[O:18])[NH:12]C1C=CON=1)[CH3:9].[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)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C1N=CN(C(N2C=[N:48][CH:47]=[CH:46]2)=O)C=1.[Na].CN([CH:54]=[O:55])C>O.Br>[Br-:1].[CH:21]1([C:27]([OH:37])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([O:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N+:5]2([CH:10]([C:47]2[CH:46]=[CH:54][O:55][N:48]=2)[C:11](=[O:18])[NH2:12])[CH3:9])=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1

Participants

9

Reactant 6

HCID 6228Dimethylformamide2×HCID 24758Sodium hydrideHCID 682631,1'-Carbonyldiimidazole2×HCID 97700(+-)-Cyclohexylphenylglycolic acidHCID 5360545SodiumHCID 131729615(1R/S,2R)-2-Hydroxymethyl-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-pyrrolidinium bromide3×

Product 1

HCID 131729617(R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide

Reagents, catalysts & solvents 2

HCID 260Hydrogen BromideSolventHCID 962WaterSolvent

Procedure

To a solution comprising (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-pyrrolidinium bromide (Intermediate B) (0.230 g, 0.718 mmol) in DMF (2 ml) is added sodium hydride (0.057 g, of a 60% dispersion in oil, 1.44 mmol) in one portion. The suspension is stirred at room temperature for 2 hours. Meanwhile, in a second reaction vessel, a solution of cyclohexyl-hydroxy-phenyl-acetic acid (0.160 g, 0.68 mmol) in DMF (2 ml) is treated with CDI (0.11 g, 0.68 mmol) in one portion. The reaction mixture is stirred at room temperature for 2 hours. The resulting CDI intermediate is added to the reaction vessel containing the sodium salt of (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-pyrrolidinium bromide and the reaction mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with water (2 ml) and 0.13 ml of HBr (48% solution in water) and purified using C-18 reverse phase column chromatography (eluent-water:acetonitrile from 0% to 100% acetonitrile) to yield the titled compound.

Workup

  1. stirringThe reaction mixture is stirred at room temperature for 2 hours
  2. stirringthe reaction mixture is stirred at room temperature for 2.5 hours
  3. custompurified

Sources & evidence

ORD record
ord-972ecac92a714ed8b1eb3ac43e64cc9b
Source dataset
uspto-grants-2012_04
Patent number
US08153669B2

Reaction notes

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