Cesium carbonate → (S)-1'-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1,4'-bipiperidin-2-one

HRID 407933Notes

Reaction equation

HRID 407933 reaction equation
[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[C:3]1=[O:22].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:70]1[CH:75]=[C:74]([CH3:76])[C:73]([S:77]([CH3:80])(=[O:79])=[O:78])=[CH:72][C:71]=1[F:81].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][C:70]4[CH:75]=[C:74]([CH3:76])[C:73]([S:77]([CH3:80])(=[O:79])=[O:78])=[CH:72][C:71]=4[F:81])[C:3]3=[O:22])[CH2:9][CH2:10]2)=[N:19][CH:18]=1)[CH3:21]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 67469754HCID 67469754, compoundHCID 67470426(S)-3-amino-1'-(5-ethylpyrimidin-2-yl)-1,4'-bipiperidin-2-one

Product 1

HCID 67470469(S)-1'-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1,4'-bipiperidin-2-oneYield 50.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

(S)-3-amino-1′-(5-ethylpyrimidin-2-yl)-1,4′-bipiperidin-2-one (220 mg, 0.725 mmol) was dissolved in toluene (7 mL) and BINAP (45.2 mg, 0.0725 mmol), 1-bromo-2-fluoro-5-methyl-4-(methylsulfonyl)benzene (Preparation B; 291 mg, 1.09 mmol) and Cs2CO3 (284 mg, 0.870 mmol) were added. The reaction was bubbled through with nitrogen for 5 minutes. Pd2 dba3 (33.2 mg, 0.0363 mmol) was added and the reaction heated to 90° C. overnight. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was purified over silica gel (90% EtOAc in hexanes) to afford a mixture. The mixture was then purified on reverse phase chromatography (15 to 95% ACN in water) to afford (S)-1′-(5-ethylpyrimidin-2-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one (178 mg, 0.364 mmol, 50.1% yield) as a white solid. Mass spectrum (apci) m/z=490.3 (M+H).

Workup

  1. customThe reaction was bubbled through with nitrogen for 5 minutes
  2. temperatureThe reaction was cooled to ambient temperature
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe residue was purified over silica gel (90% EtOAc in hexanes)
  6. customto afford a mixture
  7. customThe mixture was then purified on reverse phase chromatography (15 to 95% ACN in water)

Sources & evidence

ORD record
ord-433bb682ccea4fb699cd925658541bc5
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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