Lithium Hexamethyldisilazide → Gsk-5498A

HRID 1946367

反応式

HRID 1946367 の反応式
[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:28][C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=1[F:39]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:28][C:29]2[C:34]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[N:8]=1)=[O:5]

参加物

5

反応物 3

HCID 2733832Lithium HexamethyldisilazideHCID 27375732-(Bromomethyl)-1-fluoro-3-(trifluoromethyl)benzeneHCID 178522346HCID 178522346、化合物2 回

生成物 1

HCID 46945384Gsk-5498A

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒3 回

反応条件

温度
5 °C

実験手順

A solution of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9) (4.59 g, 20.6 mmol) in THF (45 ml) was cooled to 5° C. under nitrogen. A solution of 1.0 M lithium bis(trimethylsilyl)amide in THF (20.6 ml, 20.6 mmol) was added dropwise maintaining the temperature below 10° C. After 10 minutes a solution of 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (5.29 g, 20.6 mmol, JRD fluorochemicals Ltd) in THF (9 ml) was added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched using 1 M hydrochloric acid (50 ml). The reaction mixture was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried with magnesium sulphate, filtered and solvent removed in vacuo. The crude material was dissolved in DCM and applied to a 330 g silica cartridge. The cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min. The required fractions were combined and evaporated in vacuo, to give the title compound as a white solid (6.75 g). The white solid (6.75 g) was dissolved in ethyl acetate (70 ml) and heated to 50° C. Cyclohexane (280 ml) was then added dropwise over 20 min.

後処理

  1. temperaturemaintaining the temperature below 10° C
  2. customThe reaction was quenched
  3. extractionThe reaction mixture was extracted with ethyl acetate (2×50 ml)
  4. washThe combined organic extracts were washed with brine (50 ml)
  5. dry with materialdried with magnesium sulphate
  6. filtrationfiltered
  7. customsolvent removed in vacuo
  8. dissolutionThe crude material was dissolved in DCM
  9. washThe cartridge was eluted with 0-100% ethyl acetate in cyclohexane over 45 min
  10. customevaporated in vacuo

出典と根拠

ORDレコード
ord-228e70687ce84be0b62d5703c0948001
出典データセット
uspto-grants-2013_03
特許番号
US08399436B2

関連ノート

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