Water → 2-Tert-butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester

HRID 1751355Notes

Reaction equation

HRID 1751355 reaction equation
[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([OH:7])[CH3:6].FS([C:21]([F:26])([F:25])C(O)=O)(=O)=O.O>C(#N)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([O:7][CH:21]([F:26])[F:25])[CH3:6]

Participants

7

Reactant 3

HCID 962WaterHCID 27375162,2-Difluoro-2-(fluorosulfonyl)acetic acid2×HCID 4351132Methyl 2-{[(tert-butoxy)carbonyl]amino}-3-hydroxybutanoate

Product 1

HCID 723379412-Tert-butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl esterYield 36.1%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 6342AcetonitrileSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
45 °C

Procedure

To a mixture of 2-tert-butoxycarbonylamino-3-hydroxy-butyric acid methyl ester (630 mg, 2.70 mmol) and copper(I) iodide (105 mg, 0.55 mmol) in acetonitrile at 45° C. was added a solution of 2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) in acetonitrile (2 mL) by syringe pump over 45 minutes. The reaction was then stirred at 45° C. for 30 minutes. Another solution of 2-(fluorosulfonyl)difluoroacetic acid (0.560 mL, 5.42 mmol) in acetonitrile (2 mL) was added by syringe pump over 45 minutes at 45° C. The reaction was stirred for 30 minutes at 45° C. after the second syringe pump addition was complete. Water was carefully added to quench the reaction, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and concentrated. The crude material was purified by flash chromatography (10% ethyl acetate/hexanes) to yield 2-tert-butoxycarbonylamino-3-difluoromethoxy-butyric acid methyl ester (276 mg, 36%). 1H-NMR: 400 MHz, (CDCl3: 6.16 (t, JHF=74.0 Hz, 1H), 5.23-5.16 (br, 1H), 4.86-4.80 (m, 1H), 4.40 (br d, J=9.8 Hz, 1H), 3.76 (s, 3H), 1.46 (br s, 9H), 1.36 (d, J=6.4 Hz, 3H) ppm.

Workup

  1. stirringThe reaction was stirred for 30 minutes at 45° C.
  2. additionafter the second syringe pump addition
  3. customto quench
  4. customthe reaction
  5. customThe organic layer was separated
  6. washwashed with water and brine
  7. dry with materialdried (MgSO4)
  8. concentrationconcentrated
  9. customThe crude material was purified by flash chromatography (10% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-b2c0e32731fb4d05be3d5e24570ddc2b
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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