p-Toluenesulfonic acid → 5'-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3'-indol]-2'(1'H)-one

HRID 853848Notes

Reaction equation

HRID 853848 reaction equation
[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:40](O)[CH2:41][CH2:42][OH:43].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]12[O:43][CH2:42][CH2:41][CH2:40][O:27]1)(=[O:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 104421,3-PropanediolHCID 521998p-Toluenesulfonic acid monohydrateHCID 9821545(S)-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione

Product 1

HCID 252690145'-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3'-indol]-2'(1'H)-oneYield 61.7%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

To a rapidly and efficiently stirred suspension of 5-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2,3-dione (16.13 g, 41.7 mmol) in benzene (785 mL) was added p-toluenesulfonic acid mono-hydrate (1.58 g, 8.34 mmol, 0.2 mole % ) and 1,3 propanediol (12.2 mL, 167 mmol, 4 eq) and the mixture was heated to reflux under a Dean Stark Trap for 5 hr. Additional p-toluenesulfonic acid (1.50 g, 0.2 mole % ) was added and the mixture was heated for another 1.5 hr. After cooling in an ice bath, the black reaction mixture was washed with sat. aq. NaHCO3 (3×350 mL), water (2×500 mL), brine (3×500 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified on silica gel eluting with CH2Cl2 followed by 50/50 Pet ether/EtOAc to give the title compound as an orange solid (11.44 g, 61.7% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (ES−) m/z 443 [M−H]. MS: (ES+) m/z 445 [M+H].

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux under a Dean Stark Trap for 5 hr
  3. temperaturethe mixture was heated for another 1.5 hr
  4. temperatureAfter cooling in an ice bath
  5. washthe black reaction mixture was washed with sat. aq. NaHCO3 (3×350 mL), water (2×500 mL), brine (3×500 mL)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude product was purified on silica gel eluting with CH2Cl2

Sources & evidence

ORD record
ord-c2b30cff8b954c1d954827f98ab444cf
Source dataset
uspto-grants-2007_08
Patent number
US07256198B2

Reaction notes

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