1,3-Dibromobenzene → tert-Butyl 4-{3-[(3-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

HRID 521219Notes

Reaction equation

HRID 521219 reaction equation
[NH2:1][C:2]1[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]2([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1.C([O-])(=O)C.[K+].[Br:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)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].CC(O)C>[Br:31][C:32]1[CH:33]=[C:34]([NH:1][C:2]2[C:6]([C:7](=[O:9])[NH2:8])=[CH:5][N:4]([C:10]3([CH2:23][C:24]#[N:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]3)[N:3]=2)[CH:35]=[CH:36][CH:37]=1

Participants

7

Reactant 4

HCID 79271,3-DibromobenzeneHCID 517044Potassium AcetateHCID 11953610Di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphaneHCID 86729368tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate2×

Product 1

HCID 86729380tert-Butyl 4-{3-[(3-bromophenyl)amino]-4-carbamoyl-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
85 °C

Procedure

tert-Butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (Intermediate 35-1) (500 mg, 1.44 mmol), potassium acetate (211 mg, 2.15 mmol), 1,3-dibromobenzene (0.69 mL, 5.74 mmol) and 2-propanol (7.2 mL) were combined in a vial and purged with a stream of N2 gas for 10 minutes. Pd2(dba)3 (52 mg, 0.060 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-i-propylbiphenyl (103 mg, 0.220 mmol) were then added. The reaction vessel was capped and the reaction mixture was heated to 85° C. and allowed to stir for 16 hours. The mixture was then cooled to ambient temperature, filtered through celite, eluting with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #12-1.

Workup

  1. custompurged with a stream of N2 gas for 10 minutes
  2. customThe reaction vessel was capped
  3. temperatureThe mixture was then cooled to ambient temperature
  4. filtrationfiltered through celite
  5. washeluting with EtOAc
  6. concentrationThe filtrate was concentrated in vacuo
  7. customthe residue was purified by MPLC on silica gel (
  8. washa gradient elution of 0-10% MeOH/DCM)

Sources & evidence

ORD record
ord-2b88f3959f694078af9bcb63a6238c63
Source dataset
uspto-grants-2016_05
Patent number
US09328099B2

Reaction notes

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