Diisopropylamine → tert-Butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate

HRID 1475617Notes

Reaction equation

HRID 1475617 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[F:32].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][C:25]=1[F:32])[CH2:30][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1

Participants

8

Reactant 5

HCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 129227103-Bromo-4-fluorobenzyl BromideHCID 13676038tert-Butyl cyclopropanecarboxylateHCID 178418339Butyllithium

Product 1

HCID 58136672tert-Butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-50 °C

Procedure

Under argon, 199.5 ml (1.42 mol) of diisopropylamine were initially charged in 1300 ml of dry THF, and the mixture was cooled to −50° C. 569.1 ml (1.42 mol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise. The resulting mixture was warmed to 0° C. and then cooled to −70° C. A solution of 161.9 g (1.14 mol) of tert-butyl cyclopropanecarboxylate in 380 ml of THF was added to the reaction solution, and during the addition the temperature was kept below −60° C. After 4 h of stirring at −78° C., a solution of 262 g (0.95 mol) of 2-bromo-4-(bromomethyl)-1-fluorobenzene in 480 ml of THF was added, and the temperature was once more kept below −60° C. The reaction mixture was slowly warmed to RT overnight, after which 1.5 liters of saturated aqueous ammonium chloride solution and 3.0 liters of ethyl acetate were added. After phase separation the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 3 kg of silica gel (mobile phase cyclohexane/dichloromethane 9:1, then 5:1). This gave 189.9 g (50.4% of theory) of the title compound.

Workup

  1. temperatureThe resulting mixture was warmed to 0° C.
  2. temperaturecooled to −70° C
  3. additionduring the addition the temperature
  4. customwas kept below −60° C
  5. customwas once more kept below −60° C
  6. temperatureThe reaction mixture was slowly warmed to RT overnight
  7. customAfter phase separation the aqueous phase
  8. extractionwas extracted with ethyl acetate
  9. washThe combined organic phases were washed with saturated sodium chloride solution
  10. dry with materialdried over magnesium sulphate
  11. concentrationconcentrated under reduced pressure
  12. customThe crude product was purified by chromatography on 3 kg of silica gel (mobile phase cyclohexane/dichloromethane 9:1

Sources & evidence

ORD record
ord-07951740111b44938cd6cec8b2cc6459
Source dataset
uspto-grants-2015_04
Patent number
US09018258B2

Reaction notes

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