Ethanol → 2'-Deoxy-2',2'-difluoro-N-(1-oxo-2-propylpentyl)-cytidine

HRID 638795

반응식

HRID 638795 반응식
[F:1][C:2]1([F:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].Cl[Si](C)(C)C.[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28](O)=[O:29])[CH2:25][CH3:26].C(O)C>N1C=CC=CC=1.C(#N)C.O>[F:18][C:2]1([F:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH:15][C:28](=[O:29])[CH:27]([CH2:31][CH2:32][CH3:33])[CH2:24][CH2:25][CH3:26])=[N:13][C:11]1=[O:12]

참가 물질

8

반응물 4

HCID 702EthanolHCID 3121Valproic AcidHCID 6397ChlorotrimethylsilaneHCID 60750Gemcitabine

생성물 1

HCID 116467772'-Deoxy-2',2'-difluoro-N-(1-oxo-2-propylpentyl)-cytidine

시약·촉매·용매 3

HCID 962Water용매HCID 1049Pyridine용매2회HCID 6342Acetonitrile용매2회

반응 조건

온도
0 °C

실험 절차

Dissolve 2′,2′-difluoro-2′-deoxycytidine (10.0 g, 38.0 mmol) in anhydrous pyridine (100 mL) and cool to 0° C. while stirring under nitrogen. Add chlorotrimethylsilane (24.0 mL, 190.0 mmol) dropwise, maintaining an internal temperature <5° C. Continue stirring at 0° C. for 2 hours. In a separate flask, dissolve 2-propylpentanoic acid (6.0 g, 41.8 mmol) in anhydrous acetonitrile (100 mL). Add 1,1-carbonyldiimidazole (6.8 g, 41.8 mmol) in small portions over 30 minutes and stir for 2 hours. Add this acetonitrile solution dropwise to the pyridine solution at 0° C. and allow the reaction to come to ambient temperature. Heat the reaction at 45° C. overnight then cool to 30-35° C. and add 100 mL absolute ethanol and heat at 45° C. for 30 minutes. Add 50 mL water and heat at 45° C. for 5 hours then cool to ambient temperature and concentrate in vacuo. Partition the crude residue between ethyl acetate and water. Acidify to pH ˜2 with phosphoric acid and separate the organic layer. Back extract the aqueous layer with additional ethyl acetate. Combine the organic solutions and wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography (120 g) eluting with a gradient of 30% to 60% ethyl acetate in methylene chloride. Isolate desired product as a white crushable foam (11.2 g, 77% yield).

후처리

  1. stirringContinue stirring at 0° C. for 2 hours
  2. stirringstir for 2 hours
  3. customthe reaction
  4. customto come to ambient temperature
  5. temperatureHeat
  6. customthe reaction at 45° C. overnight
  7. temperaturethen cool to 30-35° C.
  8. temperatureheat at 45° C. for 30 minutes
  9. temperatureheat at 45° C. for 5 hours
  10. temperaturethen cool to ambient temperature
  11. concentrationconcentrate in vacuo
  12. customPartition the crude residue between ethyl acetate and water
  13. customseparate the organic layer
  14. extractionBack extract the aqueous layer with additional ethyl acetate
  15. washwash with saturated sodium bicarbonate solution and saturated sodium chloride solution
  16. dry with materialdry over magnesium sulfate
  17. concentrationconcentrate in vacuo
  18. customPurify by silica gel chromatography (120 g)
  19. washeluting with a gradient of 30% to 60% ethyl acetate in methylene chloride

출처 및 근거

ORD 기록
ord-cb3f2ead51f940e4b39d683689b69d13
출처 데이터셋
uspto-grants-2010_04
특허 번호
US07691827B2

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