Hydrochloric Acid → 3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester

HRID 2214498Notes

Reaction equation

HRID 2214498 reaction equation
[F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:24](OC)(=[O:29])[C:25]([O:27][CH3:28])=[O:26].Cl>C1COCC1>[CH3:28][O:27][C:25](=[O:26])[C:24]([OH:29])=[CH:9][C:8](=[O:10])[N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)[CH3:11]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 11120Dimethyl oxalateHCID 2733832Lithium HexamethyldisilazideHCID 21947447N-[(4-Fluorophenyl)methyl]-N-methylacetamide

Product 1

HCID 696556793-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl esterYield 80.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

N-(4-Fluoro-benzyl)-N-methyl-acetamide (3.6 grams, 20 mmol) was dissolved in 20 mL of THF and cooled to −78° C. To this was added 40 mL of 1M LiHMDS (in THF) and the resulting solution stirred for 30 min. Next dimethyl oxalate (3.5 grams, 30 mmol) dissolved in 8 mL of THF is added and the reaction stirred for 2 h at −78° C., then warmed to 0° C. and stirred an additional 30 min. To this was added 1N HCl and the mixture then extracted with EtOAc. The organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and the solvent removed. The crude product was purified by column chromatography (4×4 cm SiO2, 80:20 Hex/EtOAc) to yield 4.3 grams solid (80% yield). HRMS (M+H) calcd for C13H15NO4F: 268.0985; found: 268.0983. Anal calcd for C13H14NO4F: C, 58.42; H, 5.28; N, 5.24. found: C, 58.48; H, 5.21; N, 5.26. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3) δ: 3.00 (s), 3.86 (s), 3.89 (s), 4.55 (s), 6.29 (s), 6.31 (s), 7.00–7.24 (overlapping m, 4). 13C NMR δ; 33.43, 34.79, 49.97, 52.63, 52.97, 93.27, 93.55, 115.63, 115.80, 115.95, 116.13, 128.36, 128.42, 129.71, 129.78, 131.32, 132.03, 159.70, 161.40, 163.25, 163.35, 170.93, 171.16.

Workup

  1. additionis added
  2. stirringthe reaction stirred for 2 h at −78° C.
  3. temperaturewarmed to 0° C.
  4. stirringstirred an additional 30 min
  5. extractionthe mixture then extracted with EtOAc
  6. washThe organic layer was washed with saturated NaCl
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. customthe solvent removed
  10. customThe crude product was purified by column chromatography (4×4 cm SiO2, 80:20 Hex/EtOAc)

Sources & evidence

ORD record
ord-50973be2617248acb6da63ced58d703f
Source dataset
uspto-grants-2006_09
Patent number
US07109186B2

Reaction notes

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