Phthalimide → (3S)-tert-butyl 3-((3-chloro-4-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylate

HRID 715064Notes

Reaction equation

HRID 715064 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[C@H:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8]

Participants

6

Reactant 4

HCID 6809PhthalimideHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 118363888(35)-Tert-butyl 3-((3-chloro-4-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate

Product 1

HCID 117965489(3S)-tert-butyl 3-((3-chloro-4-fluorophenyl)(1,3-dioxoisoindolin-2-yl)methyl)pyrrolidine-1-carboxylateYield 42%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 69a/69b (364.3 mg, 1.105 mmol) in THF (5.5 mL, 0.2 M) under nitrogen was added phthalimide (178.8 mg, 1.215 mmol) and PPh3 (376.7 mg, 1.436 mmol). The reaction was cooled to 0° C. and diethyl azodicarboxylate (654.0 μL, 1.436 mmol) was added dropwise via syringe. The reaction was allowed to warm to RT and stirred for 16 h. The reaction was concentrated to dryness by rotovap, diluted to 30 mL with EtOAc and washed with water (2×30 mL) and brine (1×30 mL). The organics were isolated, dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a hexanes/acetone gradient (5 to 70% acetone) to afford 212 mg (42%) of 71a/71b as a clear oil containing approximately a 1:1 mixture of diastereomers.

Workup

  1. temperatureto warm to RT
  2. concentrationThe reaction was concentrated to dryness by rotovap
  3. additiondiluted to 30 mL with EtOAc
  4. washwashed with water (2×30 mL) and brine (1×30 mL)
  5. customThe organics were isolated
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified by SiO2 chromatography
  10. washeluting with a hexanes/acetone gradient (5 to 70% acetone)

Sources & evidence

ORD record
ord-aa0e8817588b4a04a0961ca5f27fb01c
Source dataset
uspto-grants-2015_11
Patent number
US09187462B2

Reaction notes

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