Barbituric Acid → (2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(1-methyl-1H-1,2,4-triazol-5-yl)-2,4,4a,6-tetrahydro-1H,1'H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione

HRID 578036Notes

Reaction equation

HRID 578036 reaction equation
[CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:22]([CH:23]=O)=[CH:21][C:11]3[C:12]([C:15]4[N:19]([CH3:20])[N:18]=[CH:17][N:16]=4)=[N:13][O:14][C:10]=3[C:9]=2[F:25])[CH2:5][C@@H:4]([CH3:26])[O:3]1.[NH:27]1[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]1=[O:35]>CO>[F:25][C:9]1[C:10]2[O:14][N:13]=[C:12]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][N:16]=3)[C:11]=2[CH:21]=[C:22]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:26])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:31]1([C:30](=[O:34])[NH:29][C:28](=[O:35])[NH:27][C:32]1=[O:33])[CH2:23]2

Participants

4

Reactant 2

HCID 6211Barbituric AcidHCID 86658124HCID 86658124, compound2×

Product 1

HCID 67433769(2R,4S,4aS)-11-fluoro-2,4-dimethyl-8-(1-methyl-1H-1,2,4-triazol-5-yl)-2,4,4a,6-tetrahydro-1H,1'H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(3'H)-trione

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
150 °C

Procedure

A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 537, 124 mg, 0.35 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (44.2 mg, 0.35 mmol) in methanol (3 ml) was heated at 150° C. for 1 hour in a microwave reactor. Solvent was removed and the residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% TFA). The solid was taken up in 9:1 CH2Cl2-MeOH and washed with NaHCO3 and brine. The aqueous layers were repeatedly extracted with additional 9:1 CH2Cl2-MeOH with each extract being washed with brine. The combined organic layers were dried (MgSO4) and concentrated and the residue was dissolved in THF. After removal of solvent, the solid residue was dried in vacuo at 50° C. overnight to afford desired product.

Workup

  1. customSolvent was removed
  2. customthe residue was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% TFA)
  3. washwashed with NaHCO3 and brine
  4. extractionThe aqueous layers were repeatedly extracted with additional 9:1 CH2Cl2-MeOH with each extract
  5. washbeing washed with brine
  6. dry with materialThe combined organic layers were dried (MgSO4)
  7. concentrationconcentrated
  8. dissolutionthe residue was dissolved in THF
  9. customAfter removal of solvent
  10. customthe solid residue was dried in vacuo at 50° C. overnight

Sources & evidence

ORD record
ord-0b9435c5779b43e6acfaf8bc19710f5f
Source dataset
uspto-grants-2015_05
Patent number
US09040528B2

Reaction notes

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