Triphenylphosphine → 4-[6-(4-Fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester

HRID 1020043

Reaction equation

HRID 1020043 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([O:37][CH3:38])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[NH:18][C:19]2[CH:24]=[C:23]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][C:30]=3[O:37][CH3:38])[N:22]=[CH:21][N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 3

HCID 11776TriphenylphosphineHCID 2782672(4-Fluoro-2-methoxyphenyl)boronic acidHCID 595089554-(6-Chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester

Product 1

HCID 595091074-[6-(4-Fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl esterYield 53.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 10340Sodium CarbonateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.63 g, 1.7 mmol) and 4-fluoro-2-methoxy-phenylboronic acid (0.30 g, 1.8 mmol) in saturated sodium carbonate solution (4 ml) and 1,4-dioxane (4 ml) was added palladium(II) acetate (0.076 g, 0.34 mmol) followed by triphenylphosphine (0.089 g, 0.34 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and the reaction monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(4-fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XIX) (0.42 g, 53%) as a white solid.

Workup

  1. temperatureThe resulting mixture was heated
  2. filtrationThe reaction mixture was filtered through a celite bed
  3. extractionthe filtrate was extracted with ethyl acetate (3×100 ml)
  4. customThe organic layers were separated
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes)

Sources & evidence

ORD record
ord-4219f7c21bd34deba4e736ff19c4a1bf
Source dataset
uspto-grants-2014_05
Patent number
US08716296B2

Linked notes

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