2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(5-methoxypyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one

HRID 408017Notes

Reaction equation

HRID 408017 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].Br[C:26]1[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=1.CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[CH:31]=[N:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=3)[CH2:20][CH2:19]2)[C:14]1=[O:24]

Participants

7

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 197561722-Bromo-5-methoxypyrazineHCID 23676156Sodium t-butoxideHCID 66800375(S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one

Product 1

HCID 54670619(S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(5-methoxypyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-oneYield 48%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

(S)-3-(2-Fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.050 g, 0.14 mmol), 2-bromo-5-methoxypyrazine (0.032 g, 0.17 mmol), NaOtBu (0.041 g, 0.42 mmol), Pd(OAc)2 (0.005 g, 0.02 mmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (DavePHOS) (0.017 g, 0.042 mmol) were added to an argon-filled sealable flask. Toluene (1.5 mL) was added and the mixture was purged with bubbling argon for 5 minutes. The vessel was sealed and the mixture was stirred at 110° C. overnight. The mixture was cooled to ambient temperature, diluted with THF (12 mL), and stirred for 15 minutes. The mixture was filtered through GF/F paper and concentrated. The residue was purified by silica chromatography (EtOAc) to afford (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(5-methoxypyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.031 g, 0.067 mmol, 48% yield). Mass spectrum (apci) m/z=464.2 (M+H). Optical purity was not determined.

Workup

  1. additionfilled sealable flask
  2. customthe mixture was purged with bubbling argon for 5 minutes
  3. customThe vessel was sealed
  4. temperatureThe mixture was cooled to ambient temperature
  5. additiondiluted with THF (12 mL)
  6. stirringstirred for 15 minutes
  7. filtrationThe mixture was filtered through GF/F paper
  8. concentrationconcentrated
  9. customThe residue was purified by silica chromatography (EtOAc)

Sources & evidence

ORD record
ord-cf3780c86d0c473eb45c0bcf0e0365c6
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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