(2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester → 1-(1,1-Dimethylethyl) 2-methyl (2S,4R)-4-(((4-bromo-1,3-dihydro-2H-isoindol-2-yl)carbonyl)oxy)-1,2-pyrrolidinedicarboxylate

HRID 400365Notes

Reaction equation

HRID 400365 reaction equation
[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18](C1NC=CN=1)(C1NC=CN=1)=[O:19].[Br:30][C:31]1[C:32]2[C:36]([CH:37]=[CH:38][CH:39]=1)=[CH:35][NH:34][CH:33]=2>CN(C)C(=O)C>[Br:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][N:34]([C:18]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)=[O:19])[CH2:35]2

Participants

5

Reactant 3

HCID 2734883(2S,4R)-4-Hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl esterHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 540199984-Bromoisoindole

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-pyrrolidinedicarboxylateYield 79.4%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
60 °C

Procedure

To a solution containing 0.5 g of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (2 mmol) in 5 mL of N,N-dimethylacetamide, was added 370 mg of carbonyl diimidazole (1.1 equiv.). The reaction was heated at 60° C. for 1 hr, then 400 mg of 4-bromoisoindole (2 mmol) was added. The reaction was continued at 60° C. overnight. After cooling down, the reaction mixture was extracted with 50 mL of EtOAc, and washed with water, brine, and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography on silica gel using heptanes/EtOAc (v/v 5/2), giving white solid 745 mg (79%). LC-MS: m/z=369.2 (ES+, M+1-Boc).

Workup

  1. temperatureAfter cooling down
  2. extractionthe reaction mixture was extracted with 50 mL of EtOAc
  3. washwashed with water, brine
  4. dry with materialdried over Na2SO4
  5. filtrationAfter filtration and concentration
  6. customthe residue was purified by flash column chromatography on silica gel

Sources & evidence

ORD record
ord-f5cbdbc5c43143789c91775b9e44d874
Source dataset
uspto-grants-2014_06
Patent number
US08741837B2

Reaction notes

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