Potassium Carbonate → 1-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-3-pyrrolidinecarbonitrile

HRID 1669213Notes

Reaction equation

HRID 1669213 reaction equation
[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1.BrCCCN1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:21]=[C:20]1[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17](=[O:26])[N:1]1[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([C:10]#[N:11])[CH2:6]1

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 21611N-3-BromopropylphthalimideHCID 574476861-(3-Aminopropyl)-3-pyrrolidinecarbonitrile

Product 1

HCID 577865711-[3-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-3-pyrrolidinecarbonitrileYield 46.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 3-pyrrolidinecarbonitrile (302) (Swidinsky, J., et al., J. Pharm. Sci. 1967, 56, 192-196) (4.5 g, 15.6 mmol), N-(3-bromopropyl)phthalimide (3.48 g, 13.0 mmol), and K2CO3 (2.16 g, 15.6 mmol) in DMF (20 mL) was stirred at 100° C. for 1.5 h. The solution was cooled, the solvent evaporated and the residue partitioned between water (50 mL) and EtOAc (50 mL). The organic fraction was extracted with 1 M HCl (2×50 mL) and the acidic fraction washed with Et2O (2×20 mL). The acidic fraction was made basic with dilute aqueous NH3 solution and the alkaline solution was extracted with DCM (3×25 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with EtOAc, to give phthalimide 303 (1.70 g, 46%) as a colourless oil: 1H NMR δ 7.82-7.87 (m, 2H, Harom), 7.69-7.74 (m, 2H, Harom), 3.75-3.79 (m, 2H, CH2), 2.87-2.93 (m, 2H, CH2N), 2.52-2.60 (m, 5H, CH2, CH2N, CH), 2.06-2.15 (m, 1H, CH2), 1.96-2.04 (m, 1H, CH2), 1.87 (p, J=7.0 Hz, 2H, CH2); 13C NMR δ 168.4 (2), 133.9 (2), 132.2 (2), 123.1 (2), 122.1, 57.2, 52.6 (2), 36.3, 29.1, 27.2, 26.1; HRMS (FAB+) calcd for C16H17N3O2 (M+) m/z 283.1321, found 283.1318.

Workup

  1. temperatureThe solution was cooled
  2. customthe solvent evaporated
  3. customthe residue partitioned between water (50 mL) and EtOAc (50 mL)
  4. extractionThe organic fraction was extracted with 1 M HCl (2×50 mL)
  5. washthe acidic fraction washed with Et2O (2×20 mL)
  6. extractionthe alkaline solution was extracted with DCM (3×25 mL)
  7. customthe combined organic fraction dried
  8. customthe solvent evaporated
  9. customThe residue was purified by chromatography
  10. washeluting with EtOAc

Sources & evidence

ORD record
ord-e337361a841d4548975c273a23bd1905
Source dataset
uspto-grants-2011_08
Patent number
US07989451B2

Reaction notes

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