Hydrochloric Acid → 4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester

HRID 79931

Reaction equation

HRID 79931 reaction equation
[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[Li+].[OH-].Cl.BrC[C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].C(N(CC)CC)C>CO>[C:18]([O:17][C:15]([N:6]1[CH2:7][CH:8]([CH2:10][O:11][CH:12]([F:14])[F:13])[CH2:9][CH:5]1[C:3]([O:2][CH2:1][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28])=[O:4])=[O:16])([CH3:21])([CH3:20])[CH3:19]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 74544-Bromophenacyl bromideHCID 8471TriethylamineHCID 666204384-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

Product 1

HCID 667889894-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl esterYield 94%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

4-Difluoromethoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (398 mg, 1.29 mmol) was dissolved in MeOH (8 mL) and LiOH (1 M in H2O, 2 mL, 2 mmol) was added. After stirring at RT for 5 h, the MeOH was removed under reduced pressure. The aqueous solution was poured into a separatory funnel, diluted with 1 M HCl (2 mL, 2 mmol) and extracted with DCM (3×). The combined organics were dried over MgSO4, filtered and concentrated. The residue was dissolved in MeCN (4 mL) and treated with 2,4′-dibromoacetophenone (200 mg, 0.719 mmol), and triethylamine (0.100 mL, 0.719 mmol). After stirring for 15 h, the solvent was removed. The crude residue was purified by silica column chromatography (10% to 35% EtOAc/Hex) to afford the title compound (303 mg, 94%).

Workup

  1. customthe MeOH was removed under reduced pressure
  2. additionThe aqueous solution was poured into a separatory funnel
  3. extractionextracted with DCM (3×)
  4. dry with materialThe combined organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. dissolutionThe residue was dissolved in MeCN (4 mL)
  8. stirringAfter stirring for 15 h
  9. customthe solvent was removed
  10. customThe crude residue was purified by silica column chromatography (10% to 35% EtOAc/Hex)

Sources & evidence

ORD record
ord-7e0c489f70b043a99468a4bea554aed1
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Linked notes

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