Boron trifluoride etherate → 1-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)cyclopropanamine

HRID 540753Notes

Reaction equation

HRID 540753 reaction equation
[CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][C:9]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[N:8]1)[CH3:6].B(F)(F)F.CCOCC.[OH-].[Na+]>O1CCCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)=[CH:10][C:9]([C:23]2[CH:24]=[C:25]([C:26]3([NH2:27])[CH2:2][CH2:1]3)[CH:28]=[CH:29][CH:30]=2)=[N:8]1)[CH3:6]

Participants

7

Reactant 4

HCID 8000Boron trifluoride etherateHCID 14798Sodium HydroxideHCID 671116173-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}benzonitrileHCID 178418443HCID 178418443, compound

Product 1

HCID 699326591-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)cyclopropanamineYield 54.4%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Ethylmagnesium bromide (3.0 M in diethyl ether, 4.3 mL, 13 mmol 2.0 equiv) was added to a solution of titanium (IV) isopropoxide (2.1 mL, 7.1 mmol, 1.1 equiv) and 3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}benzonitrile (2.3 g, 6.4 mmol, 1 equiv) in tetrahydrofuran (26 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 min, then the cooling bath was removed. After stirring for an additional 60 minutes, boron trifluoride diethyl etherate (1.6 mL, 13 mmol, 2.0 equiv) was added stirred for 45 minutes, then cooled to 0° C. and treated with aqueous sodium hydroxide solution (3.0 N, 40 mL). The biphasic mixture was stirred for 15 minutes, then filtered through celite with the aid of ethyl acetate. The filtrate was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (50% ethyl acetate-hexanes, followed by 10% methanol-dichloromethane) to afford 1-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)cyclopropanamine (1.35 g, 51%). Calcd (M+1)+: 388.2. Found: 388.1.

Workup

  1. customthe cooling bath was removed
  2. stirringAfter stirring for an additional 60 minutes
  3. stirringstirred for 45 minutes
  4. temperaturecooled to 0° C.
  5. stirringThe biphasic mixture was stirred for 15 minutes
  6. filtrationfiltered through celite with the aid of ethyl acetate
  7. customThe filtrate was partitioned between ethyl acetate and saturated aqueous sodium chloride solution
  8. dry with materialThe organic layer was dried over sodium sulfate
  9. filtrationThe dried solution was filtered
  10. concentrationthe filtrate was concentrated
  11. customThe residue was purified by flash-column chromatography (50% ethyl acetate-hexanes, followed by 10% methanol-dichloromethane)

Sources & evidence

ORD record
ord-3bdbd0e310c5410bb4215a0c4e7a9e03
Source dataset
uspto-grants-2014_10
Patent number
US08871796B2

Reaction notes

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