Sodium hydride → N-[4-chloro-2'-fluoro-5'-[(phenylthio)methoxy]phenyl]-3-(trifluoromethyl)glutarimide

HRID 275434Notes

Reaction equation

HRID 275434 reaction equation
[H-].[Na+].[Cl:3][C:4]1[C:9]([OH:10])=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:21])([F:20])[F:19])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1.[C:24]1([S:30][CH2:31]Cl)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:3][C:4]1[C:9]([O:10][CH2:31][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:7]([N:11]2[C:16](=[O:17])[CH2:15][CH:14]([C:18]([F:20])([F:19])[F:21])[CH2:13][C:12]2=[O:22])=[C:6]([F:23])[CH:5]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 81623Chloromethyl phenyl sulphideHCID 15767072N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide2×

Product 1

HCID 19047177N-[4-chloro-2'-fluoro-5'-[(phenylthio)methoxy]phenyl]-3-(trifluoromethyl)glutarimideYield 23%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

While kept under N2, 0.15 g (3.7 mmol, 60% dispersion in oil) sodium hydride was washed with pentanes (2×0.5 ml), then suspended in 2 ml of dry THF (freshly distilled from sodium/benzophenone). To the suspension, cooled in an ice bath, were added 1.1 g (3.4 mmol) of N-(4'-chloro-2'-fluoro-5'-hydroxyphenyl)-3-(trifluoromethyl)glutarimide (Compound 19) dissolved in 3.5 ml of dry THF (freshly distilled from sodium/benzophenone) and two 1 ml rinses of dry THF. The reaction was then allowed to warm to room temperature and stirred for 15 minutes. The flask was again cooled in an ice bath while a solution of chloromethyl phenyl sulfide (0.46 ml, 0.54 g, 3.4 mmol) in 3 ml dry THF was added dropwise. The reaction mixture was allowed to warm slowly to room temperature and stirred for about 24 hours, then warmed to 50° C. for 54 hours. The THF was evaporated in vacuo (2-10 Torr) and the reaction mixture was taken up in 12 ml anhydrous dimethylformamide. The reaction was heated to 100° C. for 8 hours then cooled to room temperature. The reaction mixture was suction filtered through a short pad of neutral alumina and rinsed with 30 ml EtOAc. The filtrate was evaporated in vacuo and the residue was dried in the vacuum oven for 12 hours (20-50 Torr, 50° C.). The resulting oil was vacuum distilled (2-10 Torr, 70° C.). The residue was chromatographed (silica gel, 1:1 hexanes/methylene chloride) to yield 350 mg (23% yield) of the desired product as a white solid, m.p. 108°-109.5° C.

Workup

  1. distillationfreshly distilled from sodium/benzophenone)
  2. temperatureTo the suspension, cooled in an ice bath
  3. distillationfreshly distilled from sodium/benzophenone) and two 1 ml rinses of dry THF
  4. additionwas added dropwise
  5. temperatureto warm slowly to room temperature
  6. stirringstirred for about 24 hours
  7. temperaturewarmed to 50° C. for 54 hours
  8. customThe THF was evaporated in vacuo (2-10 Torr)
  9. temperatureThe reaction was heated to 100° C. for 8 hours
  10. temperaturethen cooled to room temperature
  11. filtrationfiltered through a short pad of neutral alumina
  12. washrinsed with 30 ml EtOAc
  13. customThe filtrate was evaporated in vacuo
  14. customthe residue was dried in the vacuum oven for 12 hours (20-50 Torr, 50° C.)
  15. distillationdistilled (2-10 Torr, 70° C.)
  16. customThe residue was chromatographed (silica gel, 1:1 hexanes/methylene chloride)

Sources & evidence

ORD record
ord-7fb161087484408fa9aa6db7830904ec
Source dataset
uspto-grants-1995_02
Patent number
US05393735

Reaction notes

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