Lithium hydroxide, monohydrate → N,beta,beta-trimethyl-L-phenylalanyl-N1,3-dimethyl-N1-{(1S)-2-methyl-1-[(Z)-(3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl]propyl}-L-valinamide

HRID 1865739Notes

Reaction equation

HRID 1865739 reaction equation
C(OP([CH:9]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[N:10]1[CH3:16])(=O)OCC)C.O.[OH-].[Li+].[CH:20]([CH:22]([N:26]([CH3:49])[C:27]([CH:29]([NH:34][C:35](=[O:48])[CH:36]([NH:46][CH3:47])[C:37]([CH3:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]([CH3:25])[CH3:24])=O>C(O)C.O>[CH3:47][NH:46][C@H:36]([C:35]([NH:34][C@H:29]([C:27]([N:26]([CH3:49])[C@H:22](/[CH:20]=[C:9]1\[N:10]([CH3:16])[C:11](=[O:15])[NH:12][C:13]\1=[O:14])[CH:23]([CH3:24])[CH3:25])=[O:28])[C:30]([CH3:31])([CH3:32])[CH3:33])=[O:48])[C:37]([CH3:38])([CH3:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1

Participants

6

Reactant 3

HCID 168937Lithium hydroxide, monohydrateHCID 13937024Diethyl (3-methyl-2,5-dioxoimidazolidin-4-yl)phosphonateHCID 72370856N-{1-[(1-Formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide

Product 1

HCID 44393187N,beta,beta-trimethyl-L-phenylalanyl-N1,3-dimethyl-N1-{(1S)-2-methyl-1-[(Z)-(3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl]propyl}-L-valinamide

Reagents, catalysts & solvents 2

HCID 702EthanolSolvent2×HCID 962WaterSolvent

Procedure

The yield, (3-methyl-2,5-dioxo-imidazolidin-4-yl)-phosphonic acid diethyl ester (0.915 g, 3.0 mmol) in ethanol (9 mL) is added to lithium hydroxide monohydrate (139 mg, 2.1 mmol) in 0.9 ml water to give a yellow solution. It is then added to N-{1-[(1-formyl-2-methyl-propyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide (˜1 mmol, from Reference Example 12) in 3 mL ethanol. The reaction mixture is stirred at room temperature for 60 hours. Solvent is evaporated. The residue is diluted with dichloromethane/water. The aqueous layer is extracted twice with dichloromethane. The combined organic extracts are washed with brine, dried oversodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a white solid, N,beta,beta-trimethyl-L-phenylalanyl-N1,3-dimethyl-N1-{(1S)-2-methyl-1-[(Z)-(3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl]propyl}-L-valinamide: 25 mg (4%) MS (ES+): (M+H)=514.3

Workup

  1. customto give a yellow solution
  2. customSolvent is evaporated
  3. additionThe residue is diluted with dichloromethane/water
  4. extractionThe aqueous layer is extracted twice with dichloromethane
  5. washThe combined organic extracts are washed with brine
  6. dry with materialdried oversodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue is chromatographed by reverse phase HPLC (0.01% trifluoroacetic acid in water/acetonitrile)

Sources & evidence

ORD record
ord-c12bf9d16c6e4bca8a8ae12022ba53df
Source dataset
uspto-grants-2009_12
Patent number
US07626023B2

Reaction notes

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