Triphenylphosphine → (4R,5R)-4-(5-Fluoro-2-((5-fluoropyridin-3-yl)ethynyl)pyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one

HRID 2362453Notes

Reaction equation

HRID 2362453 reaction equation
Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)[C:5]([F:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:5]1[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)=[CH:7][C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)=[N:3][CH:4]=1

Participants

7

Reactant 3

HCID 11776TriphenylphosphineHCID 569723593-Ethynyl-5-fluoropyridineHCID 86673419(4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one

Product 1

HCID 69083147(4R,5R)-4-(5-Fluoro-2-((5-fluoropyridin-3-yl)ethynyl)pyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-oneYield 49.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8471TriethylamineSolvent

Conditions

Temperature
90 °C

Procedure

To a 15 ml sealable vial was added a 60:40 mixture of (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one (50 mg, 0.141 mmol) and its regioisomer in triethylamine (3 mL). To this suspension was added 3-ethynyl-5-fluoropyridine (22.17 mg, 0.183 mmol), triphenylphosphine (11.08 mg, 0.042 mmol) and copper(I) iodide (0.536 mg, 2.82 mmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (1.976 mg, 2.82 mmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by reverse phase chromatography to isolate a single peak (4R,5R)-5-(5-fluoro-2-((5-fluoropyridin-3-yl)ethynyl)pyridin-4-yl)-4-(4-fluorophenyl)oxazolidin-2-one (18.4 mg, 0.046 mmol, 49.8% yield). This single peak was still a mixture of the regioisomers. This single peak was a 65:35 mixture of regioisomers and was subsequently purified by chiral supercritical fluid chromatography Chiralpak AD-H column, 4.6×250 mm, 5 um particle size mobile phase: 35% MeOH in CO2 (w/0.1% diethylamine) column temp: 35 C flow rate: 2 mL/min., affording 1H-NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.54 (s, 1H), 8.51 (d, J=4.0, 1H), 7.79 (d, J=4.0, 1H), 7.64-7.60 (m, 1H), 7.42-7.39 (m, 2H), 7.19-7.15 (m, 2H), 6.00 (brs, 1H), 5.36 (d, J=4.0, 1H), 5.12 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=1.95 min. Mass=395.99 (MH)+.

Workup

  1. additionTo a 15 ml sealable vial was added
  2. customThe solution was degassed with nitrogen for 20 min
  3. customthe vial was sealed
  4. temperaturethe reaction was cooled to room temperature
  5. customthe solvent was evaporated in vacuo
  6. customThe crude residue was purified by reverse phase chromatography

Sources & evidence

ORD record
ord-d46d33c18ecd45f38ba6e96612b5d4be
Source dataset
uspto-grants-2014_04
Patent number
US08691821B2

Reaction notes

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