(S)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one → (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one

HRID 407979Notes

Reaction equation

HRID 407979 reaction equation
[Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].Br[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([O:27][C:28]4[CH:33]=[C:32]([F:34])[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:30][C:29]=4[F:39])[C:23]3=[O:40])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Zn].[Pd]>[F:39][C:29]1[CH:30]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]([F:34])=[CH:33][C:28]=1[O:27][C@H:24]1[CH2:25][CH2:26][N:22]([CH:19]2[CH2:20][CH2:21][N:16]([C:13]3[N:12]=[CH:11][C:10]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)=[CH:15][N:14]=3)[CH2:17][CH2:18]2)[C:23]1=[O:40]

Participants

7

Reactant 2

HCID 67469711(S)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-oneHCID 178418723HCID 178418723, compound

Product 1

HCID 54671280(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-oneYield 56.3%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 23994ZincCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
55 °C

Procedure

Pyridin-2-yl zinc(II) bromide (0.5M; 632 μL, 0.316 mmol) was added to a nitrogen purged flask. Pd(PPh3)4 (17.4 mg, 0.0151 mmol) was added followed by (S)-1-(1-(5-bromopyrimidin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (Example 90; 80 mg, 0.151 mmol) dissolved in THF (1 mL). The reaction was stirred at ambient temperature for 1 hour and 55° C. for 6 hours. Additional zinc reagent and palladium were added and the reaction stirred at 55° C. overnight. The reaction was partitioned between aqueous NH4Cl and CH2Cl2, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (95% EtOAc in hexanes) to afford (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1-(1-(5-(pyridin-2-yl)pyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (44.9 mg, 0.0848 mmol, 56.3% yield) as a pale yellow solid. Mass spectrum (apci) m/z=530.2 (M+H).

Workup

  1. stirringthe reaction stirred at 55° C. overnight
  2. customThe reaction was partitioned between aqueous NH4Cl and CH2Cl2
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified over silica gel (95% EtOAc in hexanes)

Sources & evidence

ORD record
ord-8073f7e25485413ea1a46f3cd72fe92d
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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