Sodium hydride → 2-fluoro-3-(3-fluoro-1H-pyrrol-2-yl)pyridine

HRID 869736Notes

Reaction equation

HRID 869736 reaction equation
[H-].[Na+].CC1C=CC(S(O[CH:14]2[C:18](F)([F:19])[CH:17]([C:21]3[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:16][CH2:15]2)(=O)=O)=CC=1.C1OCCOCCOCCOCCOC1.[Cl-].[NH4+]>O1CCCC1>[F:27][C:22]1[C:21]([C:17]2[NH:16][CH:15]=[CH:14][C:18]=2[F:19])=[CH:26][CH:25]=[CH:24][N:23]=1

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 3633615-Crown-5HCID 866397284,4-Difluoro-5-(2-fluoropyridin-3-yl)pyrrolidin-3-yl 4-methylbenzenesulfonate

Product 1

HCID 583498262-fluoro-3-(3-fluoro-1H-pyrrol-2-yl)pyridineYield 72%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

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. concentrationconcentrated under reduced pressure
  3. additionThe residue was diluted with ethyl acetate
  4. washwashed with 1 mol/L hydrochloric acid
  5. extractionThe separated aqueous layer was extracted again with ethyl acetate
  6. washCombined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine
  7. dry with materialdried over anhydrous magnesium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→3:1)

Sources & evidence

ORD record
ord-86dcbfc0fbd945ec989da6b30862e41d
Source dataset
uspto-grants-2015_03
Patent number
US08969387B2

Reaction notes

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