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

HRID 245548Notes

Reaction equation

HRID 245548 reaction equation
[CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:17]([CH:18]=O)=[CH:16][C:11]3[C:12]([CH3:15])=[N:13][O:14][C:10]=3[C:9]=2[F:20])[CH2:5][C@H:4]([CH3:21])[O:3]1.[NH:22]1[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]1=[O:30]>C(O)(C)C.CO>[F:20][C:9]1[C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[CH:16]=[C:17]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:21])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:26]1([C:25](=[O:29])[NH:24][C:23](=[O:30])[NH:22][C:27]1=[O:28])[CH2:18]2

Participants

5

Reactant 2

HCID 6211Barbituric AcidHCID 866580566-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde2×

Product 1

HCID 45381704(2R,4S,4aS)-rel-11-fluoro-2,4,8-trimethyl-1,2,4,4a-tetrahydro-2'H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5'-pyrimidine]-2',4',6'(1'H,3'H)-trioneYield 71%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 6-((2R,6S)-2,6-dimethylmorpholino)-7-fluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 34, 543 mg, 1.86 mmol) in isopropanol (50 ml) was added pyrimidine-2,4,6(1H,3H,5H)-trione (238 mg, 1.86 mmol), and the reaction mixture was stirred for 16 hours at 80° C. Solvent was removed and the residue was triturated with isopropanol. The solid was filtered, washed with isopropanol, and dried in vacuo. The filtrate was concentrated and purified on silica gel (30-50% EtOAc in hexanes). The product thus obtained was combined with the filtered solid in methanol and concentrated to give the title compound (528 mg, 71%) as a racemic mixture.

Workup

  1. customSolvent was removed
  2. customthe residue was triturated with isopropanol
  3. filtrationThe solid was filtered
  4. washwashed with isopropanol
  5. customdried in vacuo
  6. concentrationThe filtrate was concentrated
  7. custompurified on silica gel (30-50% EtOAc in hexanes)
  8. customThe product thus obtained
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-dfade0d224d54f2f8185f87d87160038
Source dataset
uspto-grants-2014_02
Patent number
US08658641B2

Reaction notes

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