Benzylamine → rac-Ethyl 2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate

HRID 1476067Notes

Reaction equation

HRID 1476067 reaction equation
CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][C:13]=1[F:14].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.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>[CH2:23]([NH:30][C:8]1[CH:9]=[C:10]([C@@H:15]2[CH2:17][C@H:16]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:12][C:13]=1[F:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1

Participants

9

Reactant 5

HCID 7504BenzylamineHCID 25517Ammonium ChlorideHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 123400670rac-Ethyl 2-(3-bromo-4-fluorophenyl)-trans-cyclopropanecarboxylate

Product 1

HCID 123461582rac-Ethyl 2-[3-(benzylamino)-4-fluorophenyl]-trans-cyclopropanecarboxylate

Reagents, catalysts & solvents 3

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

Conditions

Temperature
110 °C

Procedure

Under argon, 361.5 m (3.8 mmol) of sodium tert-butoxide were suspended in 12.9 ml of toluene, and 900 mg (3.1 mmol) of (+/−)-trans-ethyl 2-(3-bromo-4-fluorophenyl)cyclopropanecarboxylate, 403 mg (3.8 mmol) of benzylamine, 28.7 mg (0.03 mmol) of tris(dibenzylideneacetone)dipalladium and 19.5 mg (0.03 mmol) of rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added successively. The mixture was heated at 110° C. for 4 h. The reaction mixture was then cooled to RT, 100 ml of ethyl acetate and 50 ml of saturated ammonium chloride solution were added and the mixture was filtered through celite. The organic phase was separated off, washed with in each case 50 ml of saturated ammonium chloride solution and saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The crude product was purified by preparative HPLC. This gave 262 mg of the target compound of a purity of 66% (18% of theory).

Workup

  1. temperatureThe reaction mixture was then cooled to RT
  2. filtrationthe mixture was filtered through celite
  3. customThe organic phase was separated off
  4. washwashed with in each case 50 ml of saturated ammonium chloride solution and saturated sodium chloride solution
  5. dry with materialdried over magnesium sulphate
  6. concentrationconcentrated
  7. customThe crude product was purified by preparative HPLC

Sources & evidence

ORD record
ord-42c33c92bac34451a50d0ebd49b52796
Source dataset
uspto-grants-2015_04
Patent number
US09018414B2

Reaction notes

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