Potassium Carbonate → tert-Butyl 4-(4-(4-(benzyloxy)-4'-(trifluoromethyl)biphenyl-3-yl)pyridin-2-yl)piperazine-1-carboxylate

HRID 1619716Notes

Reaction equation

[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO.C1C(/C(/C2[C-]=CC(Cl)=CC=2)=N\O)=CC=C(Cl)C=1.C1C(/C(/C2[C-]=CC(Cl)=CC=2)=N\O)=CC=C(Cl)C=1.[Cl-].[Cl-].[Pd+2].[Pd+2].CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:40]2[CH:41]=[CH:42][C:37]([C:36]([F:47])([F:46])[F:35])=[CH:38][CH:39]=2)=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 130 °C

Procedure

tert-Butyl 4-(4-(2-(benzyloxy)-5-chlorophenyl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 116, 1.10 g, 2.29 mmol), 4-(trifluoromethyl)phenylboronic acid (866 mg, 4.58 mmol), di-μ-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino)methyl]phenyl]palladium (II) dimer (93 mg, 0.114 mmol), tri-tert-butylphosphonium tetrafluoroborate (66 mg, 0.228 mmol), potassium carbonate (635 mg, 4.60 mmol) and tetrabutyl ammonium hydroxide (1M in methanol, 0.46 mL, 0.46 mmol) were combined in a microwave vial. Dimethylformamide (12 mL) was added and the vial was sealed. The mixture was heated at 130° C. for 2 hours in a microwave and then partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, washed with brine (5 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in dimethylformamide (12 mL) and 4-(trifluoromethyl)phenylboronic acid (866 mg, 4.58 mmol), di-mu-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino)methyl]phenyl]palladium (II) dimer (93 mg, 0.114 mmol), tri-tert-butylphosphonium tetrafluoroborate (66 mg, 0.228 mmol), potassium carbonate (635 mg, 4.60 mmol) and tetrabutyl ammonium hydroxyde (1M in methanol, 0.46 mL, 0.46 mmol) were added. The mixture was heated at 130° C. for 1 hour in microwave and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oil residue was purified on silica gel by Biotage (5% to 80% ethyl acetate in heptane over 20 CV) to give the title compound as a white solid (655 mg, 48%).

Workup

customthe vial was sealed
custompartitioned between ethyl acetate (15 mL) and water (5 mL)
customThe organic layer was separated
washwashed with brine (5 mL)
dry with materialdried over anhydrous MgSO4
filtrationfiltered
concentrationconcentrated in vacuo
dissolutionThe residue was dissolved in dimethylformamide (12 mL)
temperatureThe mixture was heated at 130° C. for 1 hour in microwave
custompartitioned between ethyl acetate and water
washThe organic layer was washed with brine
dry with materialdried over anhydrous magnesium sulfate
concentrationconcentrated in vacuo
customThe oil residue was purified on silica gel by Biotage (5% to 80% ethyl acetate in heptane over 20 CV)

Sources & evidence

ORD record: ord-44921d0daf1c4c45b9360323d6ec6cb1
Source dataset: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08772293B2

Reaction notes

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