4-Methylmorpholine → 8-Tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide

HRID 1013331Notes

Reaction equation

HRID 1013331 reaction equation
[C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N[CH2:19][C:20]1[CH:25]=CC(NS(C)(=O)=O)=C(F)[CH:21]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:46]1(OC(N(C)C)=[N+](C)C)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2N=N1>CN(C=O)C>[C:20]([C:53]1[CH:52]=[CH:51][C:50]([NH:46][C:13]([C:10]2[CH2:9][C:8]3([CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:17][CH2:16]3)[O:12][N:11]=2)=[O:15])=[CH:49][CH:54]=1)([CH3:25])([CH3:21])[CH3:19]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 21097526N-(4-(aminomethyl)-2-fluorophenyl)methanesulfonamideHCID 579514498-Tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid

Product 1

HCID 579514578-Tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (120 mg, 0.51 mmol), N-(4-aminomethyl-2-fluorophenyl)methanesulphonamide (110 mg, 0.51 mmol), 4-methylmorpholine (101 mg, 1.02 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (288 mg, 0.65 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, hexane/EtOAc 2:1), the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a trans isomer (30 mg, 13% of the theoretical amount) and cis isomer (100 mg, 45% of the theoretical amount).

Workup

  1. customThe solvent was removed under vacuum
  2. customsat. aq. NaHCO3 solution and the phases were separated
  3. extractionThe aqueous phase was extracted several times with EtOAc
  4. dry with materialthe combined organic phases were dried over magnesium sulphate
  5. customthe solvent was removed under vacuum
  6. customAfter purification by column chromatography (silica gel, hexane/EtOAc 2:1)

Sources & evidence

ORD record
ord-84f9cb16e3214dde8eef56ba9ad7ac7a
Source dataset
uspto-grants-2011_07
Patent number
US07981883B2

Reaction notes

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