Sodium bis(trimethylsilyl)amide → (R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one

HRID 2209031Notes

Reaction equation

HRID 2209031 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[OH:11][C@@H:12]([C@H:14]1[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:29])[CH2:15]1)[CH3:13].[Cl:30][C:31]1[N:36]=[C:35](S(C)(=O)=O)[C:34]2[N:41]([CH:44]([F:46])[F:45])[CH:42]=[N:43][C:33]=2[CH:32]=1>CN(C=O)C>[Cl:30][C:31]1[N:36]=[C:35]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:34]2[N:41]([CH:44]([F:45])[F:46])[CH:42]=[N:43][C:33]=2[CH:32]=1

Participants

5

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 117843967(R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-oneHCID 1178440566-chloro-3-(difluoromethyl)-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine

Product 1

HCID 117843565(R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Under Ar, NaHMDS (1.0 M in THF, 0.96 mL, 0.96 mmol) was added over 30 s to a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (255 mg, 0.968 mmol) in DMF (3 mL). After stirring 10 min, the resulting mixture was added over ca. 45 s to a cooled (−20° C.) solution of 6-chloro-3-(difluoromethyl)-4-(methylsulfonyl)-3H-imidazo[4,5-c]pyridine (215 mg, 0.763 mmol) in DMF (3 mL). After stifling 15 min, the reaction was quenched with saturated NH4Cl (3 mL) and was diluted with EtOAc (20 mL) and water (20 mL). The phases were separated, and the organic layer was washed with water (30 mL) and brine (30 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (20-45% acetone in hexanes) to provide (R)-4-((R)-1-(6-chloro-3-(difluoromethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H24ClF2N4O3: 465.2; found: 464.9.

Workup

  1. additionthe resulting mixture was added over ca. 45 s to
  2. waitAfter stifling 15 min
  3. customthe reaction was quenched with saturated NH4Cl (3 mL)
  4. additionwas diluted with EtOAc (20 mL) and water (20 mL)
  5. customThe phases were separated
  6. washthe organic layer was washed with water (30 mL) and brine (30 mL)
  7. dry with materialThe organic phase was dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude residue was purified by silica gel chromatography (20-45% acetone in hexanes)

Sources & evidence

ORD record
ord-15dde4ae20d647b6b5a9db515d264f29
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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