Binap, (A+-)- → 4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-N-[1-(4-trifluoromethylsulfanyl-phenyl)-piperidin-4-yl]-butyramide

HRID 511125Notes

Reaction equation

HRID 511125 reaction equation
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.CC(C)([O-])C.[Na+].Br[C:54]1[CH:59]=[CH:58][C:57]([S:60][C:61]([F:64])([F:63])[F:62])=[CH:56][CH:55]=1.[NH:65]1[CH2:70][CH2:69][CH:68]([NH:71][C:72](=[O:92])[CH2:73][CH2:74][CH2:75][N:76]2[CH2:81][CH2:80][N:79]([C:82]3[CH:87]=[CH:86][C:85]([C:88]([F:91])([F:90])[F:89])=[CH:84][CH:83]=3)[CH2:78][CH2:77]2)[CH2:67][CH2:66]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[F:91][C:88]([F:89])([F:90])[C:85]1[CH:86]=[CH:87][C:82]([N:79]2[CH2:80][CH2:81][N:76]([CH2:75][CH2:74][CH2:73][C:72]([NH:71][CH:68]3[CH2:69][CH2:70][N:65]([C:54]4[CH:59]=[CH:58][C:57]([S:60][C:61]([F:64])([F:63])[F:62])=[CH:56][CH:55]=4)[CH2:66][CH2:67]3)=[O:92])[CH2:77][CH2:78]2)=[CH:83][CH:84]=1

Participants

8

Reactant 4

HCID 634876Binap, (A+-)-HCID 7364134-(Trifluoromethylthio)bromobenzeneHCID 23676156Sodium t-butoxideHCID 58576583N-piperidin-4-yl-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butyramide

Product 1

HCID 469469694-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-N-[1-(4-trifluoromethylsulfanyl-phenyl)-piperidin-4-yl]-butyramideYield 43.5%

Reagents, catalysts & solvents 3

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

Procedure

Tris(dibenzylideneacetone)dipalladium (13 mg; 0.01 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (26 mg; 0.04 mmol), sodium tert-butoxide (120 mg; 1.20 mmol), 1-bromo-4-trifluoromethylsulfanyl-benzene (160 mg; 0.62 mmol) and N-piperidin-4-yl-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butyramide (300 mg; 0.75 mmol, prepared in accordance with Example 75) are suspended in dry toluene (10 mL) and the mixture is irradiated in a mono-mode microwave oven for 90 minutes at 120° C. The mixture is then cooled down to room temperature, is diluted with ethyl acetate (50 mL), is filtered and the filtrate is concentrated under reduced pressure. The crude residue is then purified by column chromatography on silica gel (dichloromethane:isopropyl alcohol 9:1) to afford the desired product (155 mg; 0.27 mmol). The structure was confirmed using Protocol I-B. Calculated mass=575; observed mass=575; HPLC retention time=5.26 min.

Workup

  1. customthe mixture is irradiated in a mono-mode microwave oven for 90 minutes at 120° C
  2. filtrationis filtered
  3. concentrationthe filtrate is concentrated under reduced pressure
  4. customThe crude residue is then purified by column chromatography on silica gel (dichloromethane:isopropyl alcohol 9:1)

Sources & evidence

ORD record
ord-40924c15a021492fa87162495de762d6
Source dataset
uspto-grants-2015_08
Patent number
US09096524B2

Reaction notes

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