Dimethylformamide → 1-(1,1-Dimethylethyl) 2-methyl (2S,4R)-4-(((4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl)oxy)-1,2-pyrrolidinedicarboxylate

HRID 388224Notes

Reaction equation

HRID 388224 reaction equation
[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Cl.[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][NH:23][CH2:24]2.CCN(C(C)C)C(C)C.CN([CH:41]=[O:42])C>>[Br:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][N:23]([C:41]([O:9][C@H:7]1[CH2:6][N:5]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:8]1)=[O:42])[CH2:24]2

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 2734883(2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esterHCID 442286444-Bromo-Isoindoline HCl

Product 1

HCID 534655661-(1,1-Dimethylethyl) 2-methyl (2S,4R)-4-(((4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl)oxy)-1,2-pyrrolidinedicarboxylate

Procedure

To a solution of (2S,4R)-BOC-4-hydroxyproline methyl ester (126.3 g, 515 mmol) in DMF (960 mL) at 0° C. was added N,N′-carbonyldiimidazole (83.51 g, 515 mmol). The reaction mixture was stirred at RT for 3 hours. 4-Bromoisoindoline hydrochloride (120 g, 515 mmol) and DIPEA (96.3 mL, 540 mmol) were added, and the reaction mixture heated to 50° C. for 6 hours. The reaction mixture was then allowed to cool to RT and stirred overnight. The reaction mixture was partitioned between EtOAc (3 L) and 10% aqueous KHSO4 (6 L), the aqueous re-extracted with EtOAc (2 L) and the combined organic phases washed with 10% aqueous NaHCO3, brine, dried over Na2SO4 and solvent evaporated to a foam (239 g). LRMS (ESI) m/z 471.0 [(M+H)+; calcd for C20H26BrN2O6: 471.1].

Workup

  1. temperaturethe reaction mixture heated to 50° C. for 6 hours
  2. temperatureto cool to RT
  3. stirringstirred overnight
  4. customThe reaction mixture was partitioned between EtOAc (3 L) and 10% aqueous KHSO4 (6 L)
  5. extractionthe aqueous re-extracted with EtOAc (2 L)
  6. washthe combined organic phases washed with 10% aqueous NaHCO3, brine
  7. dry with materialdried over Na2SO4 and solvent
  8. customevaporated to a foam (239 g)

Sources & evidence

ORD record
ord-96fde5e4a59a480195ce556b2b96895f
Source dataset
uspto-grants-2013_02
Patent number
US08377873B2

Reaction notes

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