Morpholine → (3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-((1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl)-6-((1S)-1-methylpropyl)-2,5-piperazinedione

HRID 2074371Notes

Reaction equation

HRID 2074371 reaction equation
Cl.[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C@H:11]1[NH:16][C:15](=[O:17])[C@@H:14]([C@@H:18]([CH3:21])[CH2:19][CH3:20])[N:13]([CH:22]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:23](O)=[O:24])[C:12]1=[O:34].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[CH2:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[C@H:11]1[NH:16][C:15](=[O:17])[C@@H:14]([C@@H:18]([CH3:21])[CH2:19][CH3:20])[N:13]([C@H:22]([C:26]2[C:27]([CH3:33])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)[C:23]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:24])[C:12]1=[O:34]

Participants

4

Reactant 2

HCID 8083MorpholineHCID 56949593{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride2×

Product 1

HCID 11634973(3R,6R)-3-(2,3-Dihydro-1H-inden-2-yl)-1-((1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl)-6-((1S)-1-methylpropyl)-2,5-piperazinedioneYield 45%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A suspension of {(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}(2,6-dimethyl-3-pyridinyl)acetic acid hydrochloride (5.0 g, 10.3 mmol) (intermediate 5) in dry dichloromethane (50 ml) was treated with 1,1-carbonyldiimidazole (2.6 g, 16 mmol) and the reaction mixture was stirred under nitrogen for 18 hours. Morpholine (4.8 ml, 55 mmol) was added and the resultant solution was left to stand under nitrogen for 18 hours. The solvent was removed in vacuo and the residue was separated between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. This was applied to a basic alumina cartridge (240 g) and eluted using a gradient of 0-7.5% methanol in diethyl ether (9CV), 7.5-10% methanol in diethyl ether (1CV) and 10% methanol in diethyl ether (1CV). The required fractions were combined and evaporated in vacuo to give (3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethyl-3-pyridinyl)-2-(4-morpholinyl)-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione as a white solid (2.4 g, 45%).

Workup

  1. waitto stand under nitrogen for 18 hours
  2. customThe solvent was removed in vacuo
  3. customthe residue was separated between ethyl acetate and water
  4. washThe organic phase was washed with brine
  5. dry with materialdried over anhydrous magnesium sulphate
  6. customThe solvent was removed in vacuo
  7. dissolutionthe residue was dissolved in dichloromethane
  8. washeluted
  9. customevaporated in vacuo

Sources & evidence

ORD record
ord-f0ca2e6f92d448349addfac8ca0413f0
Source dataset
uspto-grants-2011_04
Patent number
US07919492B2

Reaction notes

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