Acetic Acid → alpha-(2,4-Difluorophenyl)-5-fluoro-beta-methyl-alpha-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol

HRID 865805ノート

反応式

HRID 865805 の反応式
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:35])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(O)(=O)C>C1COCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]([OH:35])([CH:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1

参加物

6

反応物 4

HCID 176Acetic AcidHCID 5880801-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanoneHCID 2724254Sodium bis(trimethylsilyl)amideHCID 190749194-Ethyl-5-fluoropyrimidine

生成物 1

HCID 5231054alpha-(2,4-Difluorophenyl)-5-fluoro-beta-methyl-alpha-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒4 回

反応条件

温度
-65 °C

実験手順

To THF (200 ml) was added sodium bis(trimethylsilyl)amide (79 ml of a 1.0M solution in THF) and the solution cooled to -65° C. under nitrogen. A solution of 4-ethyl-5-fluoropyrimidine (10 g) (see Preparation 8) in THF (100 ml) was added over 30 minutes. After stirring for 3 hours at -65° C. the thin slurry was treated with a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (17.7 g) in THF (100 ml), dropwise over 30 minutes. The solution was stirred for a further 1 hour at -65° C. and then treated with acetic acid (20 ml). After warming to -20° C. the solution was washed with water (200 ml) and the organic layer separated and combined with an ethyl acetate (200 ml) back extract of the aqueous phase. The combined organic layers were concentrated under reduced pressure to provide a solid that was triturated with diethyl ether (230 ml) and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica with 1:1 diethyl ether/ethyl acetate as the eluent. The fractions containing the title compound were combined, concentrated under reduced pressure and the residue chromatographed on silica with 1:1 ethyl acetate/hexane as the eluent. The appropriate fractions were combined and evaporated under reduced pressure to provide the purified title compound (0.82 g), m.p. 125°-127° C. Found: C,54.89; N,19.66; C16H14F3N5O requires: C,55.01; H,4.01; N,20.05%.

後処理

  1. stirringThe solution was stirred for a further 1 hour at -65° C.
  2. temperatureAfter warming to -20° C. the solution
  3. washwas washed with water (200 ml)
  4. customthe organic layer separated
  5. extractionback extract of the aqueous phase
  6. concentrationThe combined organic layers were concentrated under reduced pressure
  7. customto provide a solid
  8. customthat was triturated with diethyl ether (230 ml)
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated under reduced pressure
  11. customchromatographed on silica with 1:1 diethyl ether/ethyl acetate as the eluent
  12. additionThe fractions containing the title compound
  13. concentrationconcentrated under reduced pressure
  14. customthe residue chromatographed on silica with 1:1 ethyl acetate/hexane as the eluent
  15. customevaporated under reduced pressure
  16. customto provide the
  17. custompurified title compound (0.82 g), m.p. 125°-127° C

出典と根拠

ORDレコード
ord-8b01bd6fd8e549f2b4f98ae4e9b3613a
出典データセット
uspto-grants-1996_10
特許番号
US05567817

反応ノート

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