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 245555ノート

反応式

HRID 245555 の反応式
[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

参加物

4

反応物 2

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

生成物 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)-trione収率 81.5%

試薬・触媒・溶媒 1

HCID 702Ethanol溶媒

実験手順

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.

後処理

  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)

出典と根拠

ORDレコード
ord-ce688636365e46c7b79d6270e93da641
出典データセット
uspto-grants-2014_02
特許番号
US08658641B2

反応ノート

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