Ethyl fluoroacetate → HCID 86732164, compound

HRID 930341Notes

Reaction equation

HRID 930341 reaction equation
C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:13]([F:23])=[CH:12][N:11]=1.[F:24][CH2:25][C:26](OCC)=[O:27]>O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.C1COCC1>[Br:9][C:10]1[N:11]=[C:12]([C:26](=[O:27])[CH2:25][F:24])[C:13]([F:23])=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:15]=1

Participants

6

Reactant 3

HCID 9988Ethyl fluoroacetateHCID 2724682Lithium diisopropylamideHCID 866680682-Bromo-5-fluoro-4-(triethylsilyl)pyridine

Product 1

HCID 86732164HCID 86732164, compoundYield 94%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 22742125Tetrahydrofuran heptane ethylbenzolSolvent

Conditions

Temperature
-78 °C

Procedure

To a 3-neck 500-mL round bottomed flask was added THF (180 mL). The solvent was cooled to −78° C. and lithium diisopropylamide, (Aldrich; 40.3 mL, 81 mmol, 2.0 M solution in tetrahydrofuran/heptane/ethylbenzene) was added over 2 min. To the solution was added 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (11a, synthesized according to procedure in WO 2012/095469 A1; 18.0 g, 62.0 mmol) in 5 mL THF over 5 min. The temperature was not allowed to go above −70° C. during the addition. After 50 min, ethyl fluoroacetate (Aldrich; 7.79 mL, 81 mmol) was added over 3 min. The temperature was not allowed to go above −60° C. during the addition. The solution was stirred at −78° C. for 10 min and then the cold bath was removed and the solution was allowed to warm to −40° C. At that point the solution was poured into a solution of 1 N HCl/10% NH4Cl (1:1, 200 mL). The solution was extracted with EtOAc (3×200 mL) and the combined extracts were washed with brine (100 mL), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 20% EtOAc/hexane) afforded 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2-fluoroethanone (20.35 g, 58.1 mmol, 94% yield) as a yellow oil. MS m/z=350.0 [M+H]+. Calculated for C13H18BrF2NOSi: 349.0.

Workup

  1. additionto go above −70° C. during the addition
  2. additionto go above −60° C. during the addition
  3. customthe cold bath was removed
  4. temperatureto warm to −40° C
  5. additionAt that point the solution was poured into a solution of 1 N HCl/10% NH4Cl (1:1, 200 mL)
  6. extractionThe solution was extracted with EtOAc (3×200 mL)
  7. washthe combined extracts were washed with brine (100 mL)
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated onto silica
  10. customPurification by silica gel chromatography (Gradient: 0.0 to 20% EtOAc/hexane)

Sources & evidence

ORD record
ord-68563c4ae0d944b08c47e97248b031f5
Source dataset
uspto-grants-2016_03
Patent number
US09296734B2

Reaction notes

Loading…