Benzylamine → tert-Butyl 1-[3-(benzylamino)-4-fluorobenzyl]cyclopropanecarboxylate

HRID 626409Notes

Reaction equation

HRID 626409 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH2:20]([NH:27][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1

Participants

9

Reactant 5

HCID 7504BenzylamineHCID 25517Ammonium ChlorideHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 58136672tert-Butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate

Product 1

HCID 58136659tert-Butyl 1-[3-(benzylamino)-4-fluorobenzyl]cyclopropanecarboxylate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

Under argon and under dry conditions, 174.0 g (528.5 mmol) of tert-butyl 1-(3-bromo-4-fluorobenzyl)cyclopropanecarboxylate, 69.2 ml (634.2 mmol) of benzylamine, 4.84 g (5.29 mmol) of tris(dibenzylideneacetone)dipalladium, 60.95 g (634.2 mmol) of sodium tert-butoxide and 3.29 g (5.29 mmol) of (+/−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were suspended in 1218 ml of toluene. The reaction mixture was then stirred at 110° C. for 2.0 h. After cooling, 2.1 liters of ethyl acetate and 1.7 liters of semisaturated aqueous ammonium chloride solution were added to the reaction mixture. After phase separation, the organic phase was washed with a saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 3.7 kg of silica gel (mobile phase petroleum ether/ethyl acetate 20:1). 145.0 g (68.7% of theory) of the title compound were thus obtained.

Workup

  1. temperatureAfter cooling
  2. customAfter phase separation
  3. washthe organic phase was washed with a saturated ammonium chloride solution and saturated sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by chromatography on 3.7 kg of silica gel (mobile phase petroleum ether/ethyl acetate 20:1)

Sources & evidence

ORD record
ord-413865119daf40269784ff57989e60c4
Source dataset
uspto-grants-2016_04
Patent number
US09309198B2

Reaction notes

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