Diethyl Malonate → 2-(1-tert-Butoxycarbonyl-pyrrolidin-3-ylmethyl)-malonic acid diethyl ester

HRID 1789892Notes

Reaction equation

HRID 1789892 reaction equation
[C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([CH2:26]Br)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH2:22]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]

Participants

5

Reactant 3

HCID 7761Diethyl MalonateHCID 24758Sodium hydrideHCID 24730280tert-Butyl 3-(bromomethyl)pyrrolidine-1-carboxylate

Product 1

HCID 540037602-(1-tert-Butoxycarbonyl-pyrrolidin-3-ylmethyl)-malonic acid diethyl esterYield 45.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Diethyl malonate (1.93 mL, 12.7 mmol) was added dropwise to a solution of NaH (60%; 0.51 g, 12.8 mmol) in dry THF (15 mL) at 0° C. The mixture was stirred at room temperature for 1 h after which it was added to a refluxed mixture of 3-bromomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2.8 g, 10.6 mmol) in dry THF (30 mL). The reaction mixture was further refluxed for 19 h, and then concentrated to almost dryness. Water (1 L) was added, and the product was extracted with CH2Cl2. The combined organic phases were dried and concentrated under reduced pressure to yield 3.3 g of the crude product. Purification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32) afforded 2-(1-tert-butoxycarbonyl-pyrrolidin-3-ylmethyl)-malonic acid diethyl ester (1.64 g, 45%).

Workup

  1. temperatureThe reaction mixture was further refluxed for 19 h
  2. concentrationconcentrated to almost dryness
  3. additionWater (1 L) was added
  4. extractionthe product was extracted with CH2Cl2
  5. customThe combined organic phases were dried
  6. concentrationconcentrated under reduced pressure
  7. customto yield 3.3 g of the crude product
  8. customPurification by flash chromatography (CH2Cl2/EtOAc: 1/0→68/32)

Sources & evidence

ORD record
ord-524293e2c7514eb993aaebdfd4d8dc85
Source dataset
uspto-grants-2006_07
Patent number
US07071175B1

Reaction notes

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