Barbituric Acid → (2R,4S,4aS)-8-(3,3-difluoroazetidine-1-carbonyl)-11-fluoro-2,4-dimethyl-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 578016Notes

Reaction equation

HRID 578016 reaction equation
[F:1][C:2]1([F:28])[CH2:5][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]([CH:26]=O)[C:15]([N:18]4[CH2:23][C@@H:22]([CH3:24])[O:21][C@H:20]([CH3:25])[CH2:19]4)=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)=[O:7])[CH2:3]1.[NH:29]1[C:36](=[O:37])[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>C(O)C>[F:28][C:2]1([F:1])[CH2:3][N:4]([C:6]([C:8]2[C:12]3[CH:13]=[C:14]4[C:15](=[C:16]([F:17])[C:11]=3[O:10][N:9]=2)[N:18]2[CH2:23][C@@H:22]([CH3:24])[O:21][C@@H:20]([CH3:25])[C@@H:19]2[C:35]2([C:33](=[O:34])[NH:32][C:30](=[O:31])[NH:29][C:36]2=[O:37])[CH2:26]4)=[O:7])[CH2:5]1

Participants

4

Reactant 2

HCID 6211Barbituric AcidHCID 866580983-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde2×

Product 1

HCID 58457175(2R,4S,4aS)-8-(3,3-difluoroazetidine-1-carbonyl)-11-fluoro-2,4-dimethyl-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)-trioneYield 81.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

3-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde (Intermediate 245, 2.08 g, 5.23 mmol) was dissolved in ˜100 ml of ethanol and heated with barbituric acid (0.704 g, 5.50 mmol) at 105° C. (external temperature) for 6 days. The reaction was absorbed onto celite then purified on by silica gel chromatography using a gradient of DCM to ethyl acetate. Fractions were combined and concentrated. This material was then purified by Supercritical Fluid Chromatography (separation of diastereomers), using a Chiralpak AD, 21×250 mm, 5μ column (elution with 40% isopropanol, 60% CO2 at 60 ml/min, 40° C., and 100 bar with detection at 220 nm), to give the title compound (2.16 g, 4.26 mmol, 81%) as the first eluting compound.

Workup

  1. customThe reaction was absorbed onto celite
  2. customthen purified on by silica gel chromatography
  3. concentrationconcentrated
  4. customThis material was then purified by Supercritical Fluid Chromatography (separation of diastereomers)
  5. washa Chiralpak AD, 21×250 mm, 5μ column (elution with 40% isopropanol, 60% CO2 at 60 ml/min, 40° C., and 100 bar with detection at 220 nm)

Sources & evidence

ORD record
ord-d14534a07bdf47b4a9c02d08864a645c
Source dataset
uspto-grants-2015_05
Patent number
US09040528B2

Reaction notes

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