Sodium Carbonate → tert-butyl (3R)-3-{[4-(5-cyano-1-methyl-1H-pyrazol-4-yl)benzoyl](3-methylpyridin-2-yl)amino}piperidine-1-carboxylate

HRID 588383Notes

Reaction equation

HRID 588383 reaction equation
[CH3:1][C:2]1[C:3]([N:8]([C:22](=[O:38])[C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.I[C:40]1[CH:41]=[N:42][N:43]([CH3:47])[C:44]=1[C:45]#[N:46].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[C:45]([C:44]1[N:43]([CH3:47])[N:42]=[CH:41][C:40]=1[C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:38])=[CH:28][CH:27]=1)#[N:46]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 601366314-Iodo-1-methyl-1H-pyrazole-5-carbonitrileHCID 123439813Tert-butyl (R)-3-(N-(3-methylpyridin-2-YL)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-YL)benzamido)piperidine-1-carboxylate

Product 1

HCID 117661192tert-butyl (3R)-3-{[4-(5-cyano-1-methyl-1H-pyrazol-4-yl)benzoyl](3-methylpyridin-2-yl)amino}piperidine-1-carboxylateYield 73%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Preparation 24, tert-butyl (3R)-3-{(3-methylpyridin-2-yl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]amino}piperidine-1-carboxylate (2.67 g, 5.12 mmol), Preparation 21, 4-iodo-1-methyl-1H-pyrazole-5-carbonitrile (1.19 g, 5.12 mmol), Pd2(dba)3 (234 mg, 0.256 mmol), and XPhos (257 mg, 0.512 mmol) were dissolved in dioxane (27 mL) under nitrogen atmosphere. A solution of Na2CO3 (1.63 g, 15.4 mmol) in H2O (3 mL) was added. The reaction was heated at 80° C. for 6 h, then stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (150 mL), washed by 50% brine solution (100 mL). The separated organic phase was dried over MgSO4, concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of 15-100% EtOAc/heptane to afford tert-butyl (3R)-3-{[4-(5-cyano-1-methyl-1H-pyrazol-4-yl)benzoyl](3-methylpyridin-2-yl)amino}piperidine-1-carboxylate as a colorless solid (1.87 g, 73% yield).

Workup

  1. washwashed by 50% brine solution (100 mL)
  2. dry with materialThe separated organic phase was dried over MgSO4
  3. concentrationconcentrated
  4. customThe residue was purified by silica gel column chromatography
  5. washeluting with a gradient of 15-100% EtOAc/heptane

Sources & evidence

ORD record
ord-1e058ac30c3246a3a590c9ad07eb5e0f
Source dataset
uspto-grants-2016_01
Patent number
US09227956B2

Reaction notes

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