1,4-Dioxane → Tert-butyl 4-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate

HRID 2364568Notes

Reaction equation

HRID 2364568 reaction equation
Cl[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[C:28](=[O:31])[NH:29][CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][C:27]=1[C:28](=[O:31])[NH:29][CH3:30]

Participants

7

Reactant 4

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 447174673-Fluoro-4-(methylcarbamoyl)benzeneboronic acidHCID 58547013Tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate

Product 1

HCID 86705402Tert-butyl 4-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylateYield 88.4%

Reagents, catalysts & solvents 2

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 962WaterSolvent2×

Conditions

Temperature
90 °C

Procedure

To a round bottomed flask (RBF) was added tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (2 g, 6.72 mmol), (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (1.64 g, 8.33 mmol; Combi-Blocks), potassium phosphate (3.56 g, 16.79 mmol), Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.476 g, 0.672 mmol), and dioxane (20 mL):Water (2 mL). The mixture was stirred at 90° C. After 16 h, the reaction was allowed to cool to room temperature and poured into water (50 mL). The aqueous solution was extracted with ethyl acetate (EtOAc) (3×25 mL). The combined EtOAc layers were concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with 30-100% EtOAc in hexane, to provide tert-butyl 4-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate (2.46 g, 5.94 mmol, 88% yield), as a yellow solid.

Workup

  1. temperatureto cool to room temperature
  2. extractionThe aqueous solution was extracted with ethyl acetate (EtOAc) (3×25 mL)
  3. concentrationThe combined EtOAc layers were concentrated in vacuo
  4. customchromatographed through a Redi-Sep® pre-packed silica gel column (40 g)
  5. washeluting with 30-100% EtOAc in hexane

Sources & evidence

ORD record
ord-a646d6f454104c2faea8b154b14192f0
Source dataset
uspto-grants-2014_04
Patent number
US08691986B2

Reaction notes

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