N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-3-(trifluoromethyl)glutaramic acid → N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-5-hydroxy-3-(trifluoromethyl)pentanamide

HRID 275430Notes

Reaction equation

HRID 275430 reaction equation
[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:23])([F:22])[F:21])[CH2:16][C:17](O)=[O:18])=[C:4]([F:25])[CH:3]=1.[Na].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:24])[CH2:14][CH:15]([C:20]([F:22])([F:21])[F:23])[CH2:16][CH2:17][OH:18])=[C:4]([F:25])[CH:3]=1

Participants

4

Reactant 2

HCID 19047101N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-3-(trifluoromethyl)glutaramic acidHCID 66591377Sodium benzophenone

Product 1

HCID 19047170N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-5-hydroxy-3-(trifluoromethyl)pentanamideYield 39.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of N-(4'-chloro-2'-fluoro-5'-isopropyloxyphenyl)-3-(trifluoromethyl)glutaramic acid (4.32 g, 11.4 mmol) in 20 ml of tetrahydrofuran, (freshly distilled from sodium/benzophenone) was slowly added 10M borane-methyl sulfide complex (1.18 ml) via syringe. The temperature was maintained at 10°-20° C. with an ice bath while vigorous bubbling was evident. The mixture was allowed to warm slowly to room temperature and stirred 150 hrs while kept under nitrogen, heated to 55° C. for 6 hours, then cooled to room temperature and allowed to stand for 16 hours. The flask was cooled in an ice/water bath, then 7 ml of methanol (MeOH) were added slowly via addition funnel. The reaction mixture became too thick to continue stirring. It was allowed to warm slowly to room temperature, when the stir bar was again able to stir the mixture. The MeOH and THF were removed in vacuo (20-50 Torr) and the residue was flash chromatographed (2"×7" column, 3:1 hexanes/ethyl acetate, 75 ml fractions). Fractions 18-45 were combined and the solvent was removed in vacuo. The residue was dried in vacuo at 50° C. to yield 1.66 g (39% yield) of the pentanamide as a nearly colorless oil.

Workup

  1. temperatureThe temperature was maintained at 10°-20° C. with an ice bath
  2. customwhile vigorous bubbling
  3. temperatureheated to 55° C. for 6 hours
  4. temperaturecooled to room temperature
  5. waitto stand for 16 hours
  6. temperatureThe flask was cooled in an ice/water bath
  7. addition7 ml of methanol (MeOH) were added slowly via addition funnel
  8. stirringto continue stirring
  9. temperatureto warm slowly to room temperature
  10. stirringto stir the mixture
  11. customThe MeOH and THF were removed in vacuo (20-50 Torr)
  12. customchromatographed (2"×7" column, 3:1 hexanes/ethyl acetate, 75 ml fractions)
  13. customthe solvent was removed in vacuo
  14. customThe residue was dried in vacuo at 50° C.

Sources & evidence

ORD record
ord-b9c6ea598eca4f3fa2ce4c1bb361e6ac
Source dataset
uspto-grants-1995_02
Patent number
US05393735

Reaction notes

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