Methanol → 4,4-Difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate

HRID 880837Notes

Reaction equation

HRID 880837 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[C:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CO>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH:12]2[C:16]([F:18])([F:17])[CH:15]([C:19]3[C:20]([F:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:14][CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 4311764Sodium borohydrideHCID 583498384,4-Difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate

Product 1

HCID 866397284,4-Difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)-3,4-dihydro-2H-pyrrol-3-yl 4-methylbenzenesulfonate (18.0 g) in tetrahydrofuran (180 mL) was added sodium borohydride (3.68 g) under ice-cooling, methanol (90 mL) was further added, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate. To a suspension of sodium hydride (9.74 g) in tetrahydrofuran (100 mL) was added dropwise a solution of 4,4-difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate in tetrahydrofuran (100 mL) under ice-cooling, 15-crown-5 (32.2 g) was added, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and washed with 1 mol/L hydrochloric acid. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=9:1→3:1) to give the title compound as a colorless solid (yield 6.35 g, 72%).

Workup

  1. temperaturecooling
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. additionthe residue was diluted with ethyl acetate
  4. washwashed with water
  5. extractionThe separated aqueous layer was extracted again with ethyl acetate
  6. washCombined organic layers were washed with saturated brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-2041eacf881742438b93d034187efe6d
Source dataset
uspto-grants-2015_03
Patent number
US08993598B2

Reaction notes

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