Cesium carbonate → HCID 86708666, compound

HRID 921776Notes

Reaction equation

HRID 921776 reaction equation
Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([Cl:18])[CH:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>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]>[C:13]([O:12][C:11]([NH:10][C:5]1[C:4]([Cl:18])=[CH:3][C:2]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[C:7]([C:8]#[N:9])[CH:6]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 12682914-Amino-1-Boc-piperidineHCID 86708665HCID 86708665, compound

Product 1

HCID 86708666HCID 86708666, compoundYield 82.4%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
95 °C

Procedure

A mixture of tert-butyl (4-bromo-2-chloro-5-cyanophenyl)carbamate (150 mg, 0.452 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (118 mg, 0.588 mmol), Pd2(dba)3 (20.7 mg, 0.023 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (26 mg, 0.045 mmol), and Cs2CO3 (442 mg, 1.36 mmol) in a dried microwave vial was flushed with nitrogen. Dioxane (4 mL) was added and the vial was sealed and heated at 95° C. overnight. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and radial silica gel chromatography of eluting with hexane/EtOAc afforded tert-butyl 4-((4-((tert-butoxycarbonyl)amino)-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate (168 mg). This was dissolved in DCM (4 mL) and TFA (4 mL) was added. After 1 hr, the solvent was removed and the residue was dissolve in MeOH and applied onto an SCX column. After washing with MeOH, the product was eluted with 2 N NH3 in MeOH. Removal of the solvents left tert-butyl 4-((4-((tert-butoxycarbonyl)amino)-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate (89 mg) as an oil. A portion of this (49.6 mg, 0.198 mmol) was dissolved in DCM (1 mL) and Boc2O (0.051 ml, 0.218 mmol) and TEA (0.030 ml, 0.218 mmol) were added. After stirred at room temperature for 1 hr, the solvent was removed and radial silica gel chromatography with hexane containing 0 to 30% EtOAc afforded tert-butyl 4-((4-amino-5-chloro-2-cyanophenyl)amino)piperidine-1-carboxylate (67 mg) as a yellow oil that solidified.

Workup

  1. customwas flushed with nitrogen
  2. additionDioxane (4 mL) was added
  3. customthe vial was sealed
  4. additionThe reaction was diluted with EtOAc
  5. filtrationfiltered through celite
  6. customThe solvent was removed from the filtrate and radial silica gel chromatography
  7. washof eluting with hexane/EtOAc

Sources & evidence

ORD record
ord-ef7f8dcb43d64e878e74ccb861ec68c8
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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