Potassium bis(trimethylsilyl)amide → (2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate

HRID 1771954ノート

反応式

HRID 1771954 の反応式
[CH3:1][C:2]1[C:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:5][O:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:25][C:26]([F:49])([F:48])[CH2:27][CH2:28][C@@H:29](OS(C(F)(F)F)(=O)=O)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:6]([C@H:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:29]([CH2:28][CH2:27][C:26]([F:25])([F:48])[F:49])[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[CH:5][O:4][N:3]=1

参加物

6

反応物 3

HCID 3251421Potassium bis(trimethylsilyl)amideHCID 90079932Tert-butyl 2-(3-methylisoxazol-4-yl)acetateHCID 90086998(R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate

生成物 1

HCID 90079887(2R,3R)-1-benzyl 4-tert-butyl 3-(3-methylisoxazol-4-yl)-2-(3,3,3-trifluoropropyl)succinate収率 61%

試薬・触媒・溶媒 2

HCID 1140Toluene溶媒2 回HCID 8028Tetrahydrofuran溶媒3 回

反応条件

温度
-78 °C

実験手順

In a 250 mL round-bottomed flask, a solution of tert-butyl 2-(3-methylisoxazol-4-yl)acetate (1.75 g, 8.87 mmol) in THF (56 mL) and toluene (27 mL) was cooled in a −78° C. bath and treated with a solution of 1M KHMDS (11.09 mL, 11.09 mmol) in THF dropwise over 2 minutes via syringe. After stirring for 15 minutes at −78° C., the reaction mixture was placed in a room temperature water bath for 15 minutes and then placed in a −78° C. bath for another 15 minutes before a solution of Intermediate S5D, (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (4.55 g, 11.53 mmol) in 6 mL THF and 3 mL toluene was added over 2 minutes. The reaction mixture was stirred in −78° C. bath for 2 hours before being quenched with saturated aqueous NH4Cl and then warmed to room temperature. The mixture was diluted with brine and extracted with EtOAc. The organic layer was dried over MgSO4 filtered and concentrated. The residue was purified on silica gel column (330 g ISCO) eluting with a gradient of 0-30% EtOAc/CH2Cl2. Tubes were collected containing the product, which was concentrated to afford Intermediate S6A (2.394 g, 61% yield) containing about 30% of the (2R,3S) isomer.

後処理

  1. customwas placed in a room temperature
  2. customfor 15 minutes
  3. customplaced in a −78° C.
  4. customfor another 15 minutes
  5. additionwas added over 2 minutes
  6. stirringThe reaction mixture was stirred in −78° C. bath for 2 hours
  7. custombefore being quenched with saturated aqueous NH4Cl
  8. temperaturewarmed to room temperature
  9. additionThe mixture was diluted with brine
  10. extractionextracted with EtOAc
  11. dry with materialThe organic layer was dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe residue was purified on silica gel column (330 g ISCO)
  15. washeluting with a gradient of 0-30% EtOAc/CH2Cl2
  16. customTubes were collected
  17. additioncontaining the product, which
  18. concentrationwas concentrated
  19. customto afford Intermediate S6A (2.394 g, 61% yield)
  20. additioncontaining about 30% of the (2R,3S) isomer

出典と根拠

ORDレコード
ord-a1b7f81d44be4b178f58cc88aa8741a2
出典データセット
uspto-grants-2016_02
特許番号
US09249157B2

反応ノート

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