Cesium carbonate → (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one

HRID 407906Notes

Reaction equation

HRID 407906 reaction equation
[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:69]1[CH:74]=[C:73]([CH3:75])[C:72]([S:76]([CH3:79])(=[O:78])=[O:77])=[CH:71][C:70]=1[F:80].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]>[CH2:19]([C:16]1[CH:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:69]4[CH:74]=[C:73]([CH3:75])[C:72]([S:76]([CH3:79])(=[O:78])=[O:77])=[CH:71][C:70]=4[F:80])[C:3]3=[O:21])[CH2:8][CH2:9]2)=[N:18][CH:17]=1)[CH3:20]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 67469717(S)-3-amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-oneHCID 67469754HCID 67469754, compound

Product 1

HCID 54670243(S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-oneYield 24%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

(S)-3-Amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 34, Steps A-D; 152 mg, 0.525 mmol) was dissolved in toluene (5 mL). 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (32.7 mg, 0.0525 mmol), 1-bromo-2-fluoro-5-methyl-4-(methylsulfonyl)benzene (Preparation B; 281 mg, 1.05 mmol) and Cs2CO3 (205 mg, 0.630 mmol) were added and nitrogen bubbled through for 5 minutes. Pd2 dba3 (24.0 mg, 0.0263 mmol) was added and the reaction plunged into a 95° C. oil bath and stirred under nitrogen overnight. The reaction was cooled, concentrated, dissolved in small amount of CH2Cl2, solids filtered away and filtrate purified over silica gel (90% EtOAc in hexanes) to afford (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (59.3 mg, 0.125 mmol, 24% yield) as a tan solid. Mass spectrum (apci) m/z=476.3.

Workup

  1. customnitrogen bubbled through for 5 minutes
  2. customplunged into a 95° C.
  3. temperatureThe reaction was cooled
  4. concentrationconcentrated
  5. dissolutiondissolved in small amount of CH2Cl2, solids
  6. filtrationfiltered away
  7. customfiltrate purified over silica gel (90% EtOAc in hexanes)

Sources & evidence

ORD record
ord-8c86601d08a54948986b7d9988b9790e
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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