Cesium carbonate → 7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

HRID 2041269Notes

Reaction equation

HRID 2041269 reaction equation
C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:53][C:54]1[CH:55]=[C:56]([CH:60]([NH2:62])[CH3:61])[CH:57]=[CH:58][CH:59]=1.[Cl:63][C:64]1[CH:80]=[CH:79][C:67]2[CH2:68][CH2:69][N:70]([C:73](=[O:78])[C:74]([F:77])([F:76])[F:75])[CH2:71][CH2:72][C:66]=2[C:65]=1OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:63][C:64]1[CH:80]=[CH:79][C:67]2[CH2:68][CH2:69][N:70]([C:73](=[O:78])[C:74]([F:75])([F:77])[F:76])[CH2:71][CH2:72][C:66]=2[C:65]=1[NH:62][CH:60]([C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=1)[CH3:61]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-2×HCID 27823621-(3-fluorophenyl)ethanamineHCID 574477477-Chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Product 1

HCID 866296247-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepineYield 56%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalyst2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

Add palladium(II) acetate (27 mg, 0.12 mmol), BINAP (146 mg, 0.24 mmol), cesium carbonate (270 mg, 0.8 mmol) and (±)-1-(3-fluorophenyl)-ethylamine (230 mg, 1.6 mmol) to a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.6 mmol) in toluene (9 mL). Degas the slurry and fill with nitrogen. Heat the mixture to 95° C. for 16 h. Add additional palladium(II) acetate (0.1 equiv.) and BINAP (0.2 equiv.) and continue heating the reaction for an additional 24 h. Cool the mixture, dilute with EtOAc (50 mL) then filter through Celite®. Concentrate the filtrate and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography to obtain (±)-7-chloro-6-[1-(3-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (138 mg, 56%). GC-MS m/z: 414 (M+).

Workup

  1. customDegas the slurry
  2. temperaturecontinue heating
  3. customthe reaction for an additional 24 h
  4. temperatureCool the mixture
  5. filtrationthen filter through Celite®
  6. concentrationConcentrate the filtrate
  7. custompurify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1)

Sources & evidence

ORD record
ord-23ff112e2017459490610f252d21e3c0
Source dataset
uspto-grants-2013_11
Patent number
US08580780B2

Reaction notes

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