4-Methylmorpholine → (+/-)-6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-[1,4]diazepane-1-carboxylic acid ethyl ester

HRID 1890410Notes

Reaction equation

HRID 1890410 reaction equation
[NH2:1][CH2:2][CH2:3][N:4]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:5][CH:6]([NH:10][C:11](=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14]([OH:16])=O)[C:7](O)=[O:8].CN1CCOCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH2:25]([O:24][C:22]([N:4]1[CH2:5][CH:6]([N:10]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[C:7](=[O:8])[NH:1][CH2:2][CH2:3]1)=[O:23])[CH3:26]

Participants

5

Reactant 3

HCID 79724-MethylmorpholineHCID 199401P,P-Diphenylphosphinic azideHCID 66929928N-{2-[(2-amino-ethyl)-ethoxycarbonyl-amino]-1-carboxy-ethyl}-phthalamic acid

Product 1

HCID 68735785(+/-)-6-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-[1,4]diazepane-1-carboxylic acid ethyl esterYield 33.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 150.00 g (208.00 mmol) of N-{2-[(2-amino-ethyl)-ethoxycarbonyl-amino]-1-carboxy-ethyl}-phthalamic acid dissolved in 3 L of anhydrous dimethylformamide was added 75.50 mL (686.40 mmol) of N-methylmorpholine. The resulting mixture was stirred at room temperature for 10 min and 143.00 g (520.00 mmol) of diphenylphosphoryl azide was added. The mixture was stirred at room temperature for 36 h and evaporated to dryness. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium chloride, saturated aqueous solution of sodium hydrogen carbonate, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 96/4/0.6 led to afford 23.00 g (33%) of the desired compound.

Workup

  1. stirringThe mixture was stirred at room temperature for 36 h
  2. customevaporated to dryness
  3. dissolutionThe mixture was dissolved in dichloromethane
  4. washwashed with a saturated aqueous solution of ammonium chloride, saturated aqueous solution of sodium chloride, saturated aqueous solution of sodium hydrogen carbonate
  5. dry with materialdried over sodium sulfate
  6. customevaporated to dryness
  7. customThe residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 96/4/0.6

Sources & evidence

ORD record
ord-224189a5197d4f26abd08c4f2e75da99
Source dataset
uspto-grants-2013_08
Patent number
US08507476B2

Reaction notes

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