Boron trifluoride etherate → 1-(2-(Benzyloxy)-5-fluorophenyl)cyclopropanamine

HRID 337112Notes

Reaction equation

HRID 337112 reaction equation
[CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C(OCC)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:14]([C:15]2([NH2:16])[CH2:2][CH2:1]2)[CH:17]=1

Participants

6

Reactant 3

HCID 8000Boron trifluoride etherateHCID 582814722-(Benzyloxy)-5-fluorobenzonitrileHCID 178418443HCID 178418443, compound

Product 1

HCID 666889311-(2-(Benzyloxy)-5-fluorophenyl)cyclopropanamine

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g).

Workup

  1. temperaturewarmed to room temperature over 1.5 h
  2. stirringthe mixture was stirred for 30 min
  3. customThe reaction was quenched with 1 M HCl (400 ml)
  4. customthe aqueous layer was separated
  5. extractionThe diethyl ether layer was further extracted into 1M HCl (2×200 mL)
  6. temperatureThe combined aqueous layers were cooled in an ice bath
  7. filtrationThe resulting precipitate was filtered through celite
  8. washwashing the pad extensively with water (200 mL), dichloromethane (4×200 mL)
  9. customThe combined filtrates were separated
  10. extractionthe aqueous layer further extracted into dichloromethane (2×200 mL)
  11. dry with materialThe combined organics were dried (MgSO4)
  12. customevaporated
  13. customresidue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol)
  14. customThe basic fractions were evaporated

Sources & evidence

ORD record
ord-0967dbcaaa7c418a8aebff62019b1703
Source dataset
uspto-grants-2014_11
Patent number
US08889692B2

Reaction notes

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