Methanol → (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

HRID 2108703Notes

Reaction equation

HRID 2108703 reaction equation
Cl.CO[C:4](=[O:11])[C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.C(OC([NH:32][C@H:33]([CH:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38]1)[C:34]([OH:36])=O)=O)C1C=CC=CC=1.C([O:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[N+:60]#[C-:61])C1C=CC=CC=1.C[OH:63]>C(N(CC)CC)C>[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]([N:6]1[C@H:5]([CH2:7][CH:8]([CH3:9])[CH3:10])[C:4](=[O:11])[NH:32][C@H:33]([CH:37]2[CH2:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:45]2)[C:34]1=[O:36])[C:61]([NH:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[OH:53])=[O:63]

Participants

7

Reactant 5

HCID 887MethanolHCID 737702,4-DifluorobenzaldehydeHCID 51261571-(Benzyloxy)-2-isocyanobenzeneHCID 11600782D-Leucine Methyl Ester HydrochlorideHCID 11631222(R)-Benzyloxycarbonylamino-indan-2-yl-acetic acid

Product 1

HCID 11649656(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Procedure

To a solution of (D)-leucine methyl ester hydrochloride (1.45 g) in methanol (10 ml) was added triethylamine (1.12 ml) and 2,4-difluorobenzaldehyde (0.875 ml). The mixture was stirred for 3 days before (2R)-[(benzyloxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (2.6 g) and 2-benzyloxyphenylisocyanide (1.76 g) were sequentially added. The reaction mixture was left to stand for 24 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate (200 ml) and water (200 ml). The organic phase was washed with brine. To this solution was added palladium on carbon (2.0 g) and acetic acid (10 ml) and the reaction mixture was stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite and washed with water (3×100 ml), saturated sodium bicarbonate solution, brine and dried over magnesium sulphate. The solvent was evaporated in vacuo. The crude product was purified by column chromatography (silica) eluting with ethyl acetate: cyclohexane (50% to 66%) to give (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (2.0 g).

Workup

  1. additionwere sequentially added
  2. waitThe reaction mixture was left
  3. customThe solvent was removed in vacuo
  4. customthe residue was separated between ethyl acetate (200 ml) and water (200 ml)
  5. washThe organic phase was washed with brine
  6. additionTo this solution was added palladium on carbon (2.0 g) and acetic acid (10 ml)
  7. filtrationThe mixture was filtered through Celite
  8. washwashed with water (3×100 ml), saturated sodium bicarbonate solution, brine
  9. dry with materialdried over magnesium sulphate
  10. customThe solvent was evaporated in vacuo
  11. customThe crude product was purified by column chromatography (silica)
  12. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-40189f8beedf4f438a889b6b07dc9b90
Source dataset
uspto-grants-2009_04
Patent number
US07514437B2

Reaction notes

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