Chloroiodomethane → (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride

HRID 347659Notes

Reaction equation

HRID 347659 reaction equation
[C:1]1([C@@H:7]([N:9]2[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]([O:17]C)=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:20][Cl:21].C([N-]C(C)C)(C)C.[Li+].[NH4+].[Cl-]>C1COCC1>[Cl-:21].[O:17]=[C:15]1[CH2:14][C@@H:11]2[CH2:10][N+:9]([C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH3:8])([CH2:13][CH2:12]2)[CH2:20]1

Participants

6

Reactant 4

HCID 11644ChloroiodomethaneHCID 25517Ammonium ChlorideHCID 2724682Lithium diisopropylamideHCID 59984924Methyl {(3R)-1-[(1S)-1-phenylethyl]pyrrolidin-3-yl}acetate

Product 1

HCID 24774186(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chlorideYield 36.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of (3R)-methyl 1-[(S)-1-phenylethly]pyrrolidine-3-acetate (25.72 g, 104.0 mmol) in THF (265 mL) was cooled under N2 in a CO2/acetone bath. Next, ICH2Cl (22.7 mL, 312.0 mmol) was added, and the mixture stirred for 30 min. A solution of 2.0M lithium diisopropylamide (heptane/THF/ethylbenzene, 156 mL, 312 mmol) was added slowly over 30 min. The internal temperature reached a maximum of −40° C. during this addition. After 1 h, sat. NH4Cl (100 mL) was added and the mixture was allowed to warm to rt. The organic layer was separated, dried (MgSO4), filtered and concentrated. The resulting red-brown foam was chromatographed (300 g SiO2, CHCl3—MeOH—NH4OH (89:10:1) followed by CHCl3—MeOH (3:1). The product fractions were pooled and concentrated to afford (5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride (10.12 g) as a tan foam (MS (ESI+) m/z 230.1 (M+H+). This foam (10.1 g, 38 mmol) was taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) added and the mixture was hydrogenated (45 psi) overnight. The mixture was filtered and re-subjected to the reduction conditions (9.1 g, 10% Pd/C, 50 psi). After 5 h, TLC indicated the consumption of the (SR)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride. The mixture was filtered, concentrated and triturated (minimal iPrOH) to give 3.73 g in two crops, as an off-white solid: [α]25D=33 (c 0.97, DMSO). MS (EI) m/z 125 (M+).

Workup

  1. customa maximum of −40° C.
  2. additionduring this addition
  3. waitAfter 1 h
  4. customThe organic layer was separated
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting red-brown foam was chromatographed (300 g SiO2, CHCl3—MeOH—NH4OH (89:10:1)
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-a7315820dac1480cb9e0869d0f3f3e39
Source dataset
uspto-grants-2007_02
Patent number
US07176198B2

Reaction notes

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