Cesium carbonate → 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one

HRID 1880133Notes

Reaction equation

HRID 1880133 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:36][N:35]([CH3:37])[C:34](=[O:38])[CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:36][N:35]([CH3:37])[C:34](=[O:38])[CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]

Participants

5

Reactant 3

HCID 10796Cesium carbonateHCID 59326874(1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanoneHCID 59327018HCID 59327018, compound

Product 1

HCID 593268734-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-oneYield 61%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
140 °C

Procedure

To a mixture of cesium carbonate (563 mg, 1.73 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.381 g, 1.60 mmol), and 4-(2-fluoropyridin-3-yl)-1-methylpyrrolidin-2-one (0.131 g, 0.675 mmol) was added NMP (2 mL). The reaction mixture was degassed and heated to 140° C. for 11 h. The mixture was cooled to room temperature and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (4×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) gave 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one (0.169 g, 0.410 mmol, 61% yield) as an off-white solid. MS m/z: 413.1 (M+1). The mixture of enantiomers was separated by preparatory SFC (Chiralcel OJH (21×250 mm), 25% EtOH/0.2% diethylamine) to afford the individual enantiomers (R)-4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one and (S)-4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylpyrrolidin-2-one. MS (ESI, pos. ion) m/z: 413.1 (M+1). IC50 (uM) +++++.

Workup

  1. customThe reaction mixture was degassed
  2. temperatureThe mixture was cooled to room temperature
  3. additiondiluted with EtOAc and water
  4. extractionThe aqueous phase was extracted with EtOAc (4×)
  5. washthe combined organic extracts were washed with brine (1×)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes)

Sources & evidence

ORD record
ord-5933a951d6f840448a3d20b6a35845af
Source dataset
uspto-grants-2012_11
Patent number
US08318718B2

Reaction notes

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