Methyl iodide → 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester

HRID 860658Notes

Reaction equation

HRID 860658 reaction equation
[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[CH:25]([N-]C(C)C)(C)C.[Li+].CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:25]

Participants

6

Reactant 4

HCID 6328Methyl iodideHCID 12679HexamethylphosphoramideHCID 2724682Lithium diisopropylamideHCID 58765789(5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester

Product 1

HCID 587658182-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl esterYield 34%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.25 mmol) is dissolved in anhydrous tetrahydrofuran (200 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (6.63 mL of 2M soln., 13.25 mmol) is slowly added to the solution at room temperature. This is allowed to stir under nitrogen for 6 hours at room temperature. Hexamethylphosphor-amide (9.2 mL, 53 mmol) is added to the reaction followed by methyl iodide (1.74 mL, 26.5 mmol), added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester (1.6 g, 4.51 mmol) is isolated in 34% yield after column chromatography. The racemic 2-[5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-propionic acid methyl ester is resolved on a Chiralpak AD column (4.6×150 mm). Eluted with 15% 3A alcohol in heptane with 0.2% dimethy-ethylamine at 0.6 mL per minute with detection at 260 nm and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 98.9% ee; isomer 2, 96.4% ee).

Workup

  1. stirringto stir under nitrogen for 6 hours at room temperature
  2. additionadded in one portion
  3. stirringto stir under nitrogen at room temperature overnight
  4. customThe solution is quenched with a saturated solution of ammonium chloride
  5. additiondiluted with ethyl acetate
  6. additionenough water added
  7. dissolutionto dissolve the solids
  8. customThe two phases are separated
  9. washthe organic layer is washed with water and brine
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-c9ae2020875043519b12c58e24b74d3b
Source dataset
uspto-grants-2006_12
Patent number
US07153878B2

Reaction notes

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