Cesium carbonate → (S)-benzyl 4-(3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate

HRID 407885Notes

Reaction equation

HRID 407885 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]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:71]1[CH:76]=[C:75]([CH3:77])[C:74]([S:78]([CH3:81])(=[O:80])=[O:79])=[CH:73][C:72]=1[F:82].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]>[F:82][C:72]1[CH:73]=[C:74]([S:78]([CH3:81])(=[O:80])=[O:79])[C:75]([CH3:77])=[CH:76][C:71]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 67469754HCID 67469754, compoundHCID 86688074(S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate

Product 1

HCID 86688080(S)-benzyl 4-(3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylateYield 76.3%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

(S)-Benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (750 mg, 2.36 mmol) (Preparation E, Step D) was dissolved in toluene (20 mL). Racemic Binap (147 mg, 0.236 mmol), 1-bromo-2-fluoro-5-methyl-4-(methylsulfonyl)benzene (947 mg, 3.54 mmol) and Cs2CO3 (924 mg, 2.84 mmol) were added and the reaction was bubbled through with nitrogen for 5 minutes. Pd2 dba3 (108 mg, 0.118 mmol) was added and the reaction plunged into 95° C. oil bath overnight. The reaction was cooled to ambient temperature, filtered and concentrated. The residue was purified over silica gel (50 to 100% EtOAc in hexanes) to afford (S)-benzyl 4-(3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (906 mg, 1.80 mmol, 76.1% yield) as a tan solid.

Workup

  1. customthe reaction was bubbled through with nitrogen for 5 minutes
  2. customplunged into 95° C.
  3. customovernight
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified over silica gel (50 to 100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-6a20f8561a9c460b8e8dd65b76e83990
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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