4-Toluenesulfonyl chloride → (S)-1-Benzyl-3-[(P-tolylsulfonyl)oxy]pyrrolidine

HRID 2405039Notes

Reaction equation

HRID 2405039 reaction equation
[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CC(OC)(C)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 73974-Toluenesulfonyl chlorideHCID 9237DabcoHCID 2733875(S)-(-)-1-Benzyl-3-pyrrolidinol

Product 1

HCID 10382042(S)-1-Benzyl-3-[(P-tolylsulfonyl)oxy]pyrrolidineYield 94.4%

Reagents, catalysts & solvents 1

HCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of (S)-1-benzyl-3-pyrrolidinol (44.3 g, 0.25 mol) and 1,4-diazabicyclo[2.2.2]octane (33.7 g, 0.3 mol) in 250 mL of MTBE under nitrogen at 0° C., was added p-toluenesulfonyl chloride (52.4 g, 0.275 mol) portion-wise over 20 minutes. The mixture was stirred at 0° C. for 1 hour. The ice bath was removed and the mixture was stirred at ambient temperature overnight (20±5 hours). EtOAc (100 mL) was added, followed by saturated aqueous sodium bicarbonate solution (250 mL). The resulting mixture was stirred at ambient temperature for 1 hour. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate solution (250 mL); saturated aqueous NH4Cl solution (250 mL); saturated aqueous NaCl solution (250 mL); and then dried over sodium sulfate (80 g). The sodium sulfate was filtered off and washed with EtOAc (20 mL) and the solvent was removed in vacuo to give 78.2 g of intermediate (1a) as an off-white solid (94% yield). HPLC analysis was conducted using a YMC ODSA C18 4.6×50 mm column, having a 5.0 micron particle size. Detection was by UV absorbance at 220 nm. The mobile phases employed were as follows (percentage by volume): A: MeOH/water/TFA (10/90/0.1; and B: MeOH/water/TFA (90/10/0.1). Using a flow rate of 4.0 mL/min of 0 to 100% B in A over 5 minutes, this intermediate was determined to have a purity of 95%.

Workup

  1. customThe ice bath was removed
  2. stirringthe mixture was stirred at ambient temperature overnight (20±5 hours)
  3. additionEtOAc (100 mL) was added
  4. stirringThe resulting mixture was stirred at ambient temperature for 1 hour
  5. customThe layers were separated
  6. washthe organic layer was washed with saturated aqueous sodium bicarbonate solution (250 mL)
  7. dry with materialand then dried over sodium sulfate (80 g)
  8. filtrationThe sodium sulfate was filtered off
  9. washwashed with EtOAc (20 mL)
  10. customthe solvent was removed in vacuo

Sources & evidence

ORD record
ord-18188aa64dd5495fabc3834860810664
Source dataset
uspto-grants-2014_08
Patent number
US08802856B2

Reaction notes

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