Morpholine → HCID 131732924, compound

HRID 2168841Notes

Reaction equation

HRID 2168841 reaction equation
[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:24]1([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[NH2:40][C@H:41]([C:45]([O:47]CC=C)=[O:46])[CH:42]([CH3:44])[CH3:43].N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[C:24]1([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[NH2:40][C@H:41]([C:45]([OH:47])=[O:46])[CH:42]([CH3:44])[CH3:43]

Participants

5

Reactant 2

HCID 8083MorpholineHCID 131732923HCID 131732923, compound

Product 1

HCID 131732924HCID 131732924, compoundYield 75.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

Cbz-Asp(O-tBu)-3-(1-naphtyl)-L-alanine-Val-OAllyl (1 g; 1.51 mmol) was co-evaporated with THF to dryness (2*10 ml), then dissolved under argon in dry THF (18 ml, inhibitor free). The solvent was degassed three times under argon (3 min+2+2) before dropwise addition of morpholine (0.658 ml, 5 eq) followed with addition of Tetrakis in one shot (174 mg, 0.1 eq). The mixture was purged under argon for 3 min. the reaction was carried out in the absence of light and at room temperature for 30 minutes. It was then diluted with ether (18 ml) followed with citric acid 0.5M (18 ml). The mixture was stirred for 3 minutes, then extracted. The aqueous layer was washed with ether (3*18 ml) then combined, dried with MgSO4. The solvent was evaporated to dryness. The crude was purified on C-18 column 50 g (pH: 3.5; gradient: 10 to 100° A) MeOH/Water; 4 ml methanol injection volume) to get 0.75 g of the desired product (second pic). NMR 1H (CD3OD, 500 MHz) δ 8.20 (d, 1H, J=8.5 Hz); 7.85 (d, 1H, J=8.1 Hz); 7.75-7.72 (m, 1H); 7.56-7.46 (m, 2H); 7.37-7.27 (m, 7H); 5.09 (q, 2H, J=12.35 Hz); 4.85 (m, 1H); 4.47-4.44 (m, 1H); 4.30 (d, 1H, J=5.8 Hz); 3.68 (dd, 1H, J=14.10; 5.80 Hz); 3.43-3.37 (m, 1H); 2.66 (dd, 1H, J=16.30; 5.9 Hz); 2.46 (dd, 1H, J=16.20; 8.1 Hz); 2.19-2.12 (m. 1H); 1.41 (s, 9H); 0.96 (d, 6H, J=6.80 Hz).

Workup

  1. customThe solvent was degassed three times under argon (3 min+2+2)
  2. customThe mixture was purged under argon for 3 min. the reaction
  3. additionIt was then diluted with ether (18 ml)
  4. extractionextracted
  5. washThe aqueous layer was washed with ether (3*18 ml)
  6. dry with materialdried with MgSO4
  7. customThe solvent was evaporated to dryness
  8. customThe crude was purified on C-18 column 50 g (pH: 3.5
  9. custom10 to 100°

Sources & evidence

ORD record
ord-000d41324cbd45239f44445dc7365ba3
Source dataset
uspto-grants-2015_06
Patent number
US09045524B2

Reaction notes

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