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

HRID 911383Notes

Reaction equation

HRID 911383 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.C1(C2SC(C(N)C)=CC=2)C=CC=CC=1.[Cl:77][C:78]1[CH:94]=[CH:93][C:81]2[CH2:82][CH2:83][N:84]([C:87](=[O:92])[C:88]([F:91])([F:90])[F:89])[CH2:85][CH2:86][C:80]=2[C:79]=1OS(C(F)(F)F)(=O)=O>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[Cl:77][C:78]1[CH:94]=[CH:93][C:81]2[CH2:82][CH2:83][N:84]([C:87](=[O:92])[C:88]([F:89])([F:91])[F:90])[CH2:85][CH2:86][C:80]=2[C:79]=1[NH:62][CH:60]([C:56]1[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=1)[CH3:61]

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-2×HCID 27823621-(3-fluorophenyl)ethanamineHCID 30320191-(5-Phenylthiophen-2-yl)ethan-1-amineHCID 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 78%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

Add tris(dibenzylideneacetone)dipalladium(0) (3.4 g, 3.8 mmol), BINAP (4.7 g, 7.5 mmol), cesium carbonate (8.6 g, 26.3 mmol) and 1-(3-fluorophenyl)-ethylamine Isomer 2 (5.8 g, 41.3 mmol) to a solution of 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (8.0 g, 18.8 mmol) in toluene (225 mL). Degas the slurry and fill with nitrogen. Heat the mixture to 95° C. for 8 h. Add additional tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv.), and BINAP (0.2 equiv.). Continue heating the reaction for an additional 16 h. Cool the mixture, dilute with EtOAc (200 mL) then filter thru Celite®. Concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) 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 (6.0 g, 78%). GC-MS m/z: 414 (M+).

Workup

  1. customDegas the slurry
  2. temperatureContinue heating
  3. customthe reaction for an additional 16 h
  4. temperatureCool the mixture
  5. filtrationthen filter
  6. concentrationConcentrate in vacuo
  7. custompurify by chromatography on silica gel eluting with hexane/EtOAc (9:1)

Sources & evidence

ORD record
ord-78879a9bcc5c4a27a19fd3ab77b1e197
Source dataset
uspto-grants-2011_09
Patent number
US08022062B2

Reaction notes

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