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 578016노트

반응식

HRID 578016 반응식
[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

참가 물질

4

반응물 2

HCID 6211Barbituric AcidHCID 866580983-(3,3-difluoroazetidine-1-carbonyl)-6-((2R,6R)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-5-carbaldehyde2회

생성물 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)-trione수율 81.5%

시약·촉매·용매 1

HCID 702Ethanol용매

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-d14534a07bdf47b4a9c02d08864a645c
출처 데이터셋
uspto-grants-2015_05
특허 번호
US09040528B2

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