1,1'-Carbonyldiimidazole → (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid

HRID 45617

Reaction equation

HRID 45617 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:20]1[C@H:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:24](=[O:30])[NH:23][C@H:22]([CH:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)[C:21]1=[O:40])[C:10](NC1C=CC=CC=1O)=[O:11].C(N1C=CN=C1)(N1C=CN=C1)=[O:42]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:20]1[C@H:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:24](=[O:30])[NH:23][C@H:22]([CH:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)[C:21]1=[O:40])[C:10]([OH:42])=[O:11]

Participants

4

Reactant 2

HCID 682631,1'-CarbonyldiimidazoleHCID 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

Product 1

HCID 68844874(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acidYield 69%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

(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 (2.650 g) was stirred in dichloromethane (20 ml) and carbonyldiimidazole (1.178 g) was added. the mixture was left at room temperature for 16 hours then the solvent was removed under reduced pressure. The residue was then taken up in 1:1 acetone:water (v/v) (80 ml) and left at room temperature for 30 minutes. The bulk of the acetone was then removed under reduced pressure and the residue was partitioned between dichloromethane and 0.5M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified (Biotage™ flash chromatography column, 90 g silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to afford (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid as a colourless solid 1.524 g as a mixture of epimers.

Workup

  1. customthe solvent was removed under reduced pressure
  2. waitwater (v/v) (80 ml) and left at room temperature for 30 minutes
  3. customThe bulk of the acetone was then removed under reduced pressure
  4. customthe residue was partitioned between dichloromethane and 0.5M hydrochloric acid
  5. customThe organic phase was separated (hydrophobic frit)
  6. customevaporated under reduced pressure
  7. customThe crude product was purified
  8. wash(Biotage™ flash chromatography column, 90 g silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1)

Sources & evidence

ORD record
ord-6e083c1a5e6148538aabf28d53f75cd1
Source dataset
uspto-grants-2013_09
Patent number
US08541579B2

Linked notes

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