Dimethylamine → (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide

HRID 2108704Notes

Reaction equation

HRID 2108704 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:44]2)[C:33]1=[O:52])[C:22]([NH:24][C:25]1C=CC=CC=1O)=[O:23].CNC.O1CCCC1>ClCCl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@H:21]([N:32]1[C@H:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:36](=[O:42])[NH:35][C@H:34]([CH:43]2[CH2:44][C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:51]2)[C:33]1=[O:52])[C:22]([N:24]([CH3:1])[CH3:25])=[O:23]

Participants

6

Reactant 4

HCID 674DimethylamineHCID 8028TetrahydrofuranHCID 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 11465834(2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamideYield 62%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Carbonyldiimidazole (4.80 g, 1.54 equiv.) was suspended in anhydrous dichloromethane (40 mL) and the suspension was left at room temperature for 15 minutes. (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 (10.50 g, pre-dried in vacuo over P4O10 for 24 hours) was then added with stirring and the resultant solution was stirred at room temperature for 6 hours. The resulting yellow solution was then treated with a 2.0M solution of dimethylamine in tetrahydrofuran (54 mL, 5.6 equiv.) and the resulting mixture was stirred at room temperature for 16 hours. The solvents plus residual dimethylamine were removed under reduced pressure and the reaction mixture was taken up in dichloromethane (200 mL) and washed with 1M hydrochloric acid (200 mL). The organic phase was separated using a hydrophobic frit and was evaporated under reduced pressure to ca. 50 mL. The crude product was applied to 4×90 g silica Biotage™ columns on a Quad 3 system; each column being eluted with (i) 2:1 v/v ethyl acetate:cyclohexane (12×50 mL fractions), (ii) ethyl acetate (12×50 mL fractions), (iii) 9:1 v/v ethyl acetate:methanol to give (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (5.753 g, 62%) as a colourless solid.

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 16 hours
  2. customThe solvents plus residual dimethylamine were removed under reduced pressure
  3. washwashed with 1M hydrochloric acid (200 mL)
  4. customThe organic phase was separated
  5. customwas evaporated under reduced pressure to ca. 50 mL
  6. washeach column being eluted with (i) 2:1 v/v ethyl acetate

Sources & evidence

ORD record
ord-527a05d228244d7aa5507bac8a1732d6
Source dataset
uspto-grants-2009_04
Patent number
US07514437B2

Reaction notes

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