Potassium Carbonate → 1-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate

HRID 383973Notes

Reaction equation

HRID 383973 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH:44](Br)[CH3:45])(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([O:12][CH:44]([O:43][C:40](=[O:42])[CH3:41])[CH3:45])=[O:11]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 111375051-Bromoethyl acetateHCID 11590614(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic Acid

Product 1

HCID 574390331-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic acid (example 22) (0.130 g) was stirred in anhydrous DMF (1 mL) and anhydrous potassium carbonate (0.020 g, 0.5 eq.) was added. The mixture was stirred at room temperature for 1 hour then cooled to −10° C. (ice-salt bath). The heterogeneous mixture was treated with 1-bromoethyl acetate (0.120 mL, excess) and stirred for 3.5 hours keeping the bath temperature between −10 and −5° C. It was then partitioned between DCM and 1M HCl aq. (20 mL each). The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give a purple gum; this was purified by SPE cartridge (5 g, silica eluted with (i) cyclohexane×2, (ii) DCM×2, (iii) diethyl ether×2, (iv) ethyl acetate×2, (v) methanol×2 to give 1-(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate (0.081 g) as a yellow foam.

Workup

  1. stirringstirred for 3.5 hours
  2. customthe bath temperature between −10 and −5° C
  3. customIt was then partitioned between DCM and 1M HCl aq. (20 mL each)
  4. customThe organic phase was separated (hydrophobic frit)
  5. customevaporated under reduced pressure
  6. customto give a purple gum
  7. customthis was purified by SPE cartridge (5 g, silica
  8. washeluted with (i) cyclohexane×2, (ii) DCM×2, (iii) diethyl ether×2, (iv) ethyl acetate×2, (v) methanol×2

Sources & evidence

ORD record
ord-e577615965f147c6a7bf8682d581eb97
Source dataset
uspto-grants-2013_02
Patent number
US08367673B2

Reaction notes

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