Dimethyl Sulfate → (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propionic acid methyl ester

HRID 23211Notes

Reaction equation

HRID 23211 reaction equation
[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].S(OC)(O[CH3:29])(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:29][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1

Participants

6

Reactant 4

HCID 6497Dimethyl SulfateHCID 168937Lithium hydroxide, monohydrateHCID 516892Sodium BicarbonateHCID 27790093,5-Difluoro-L-phenylalanine, N-BOC protected

Product 1

HCID 9836527(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propionic acid methyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet and thermocouple is added (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (1,40 g, 0.133 moles, 1 equivalent) followed by THF (240 mL). Lithium hydroxide monohydrate (5.6 g, 0.133 moles, 1 equivalent) is added in a single portion and is allowed to stir for 30 min at which time, the contents are cooled to 0°. Once cooled, dimethyl sulfate (12.6 mL, 0.133 moles, 1 equivalent) is added dropwise via syringe and then stirred for 30 min. The mixture is then heated to about 50° and monitored (by HPLC) until 90% conversion had been achieved. At that time, the mixture is cooled to below 20° (solids form). The mixture is then poured into sodium bicarbonate (200 mL), stirred for 15 min then extracted with methyl t-butyl ether (200 mL). The phases are separated and the aqueous layer is extracted with methyl t-butyl ether (2×200 mL). The combined organic phases are washed with water (400 mL) dried over sodium sulfate, filtered and concentrated under reduced pressure to give a solid. This material is then recrystallized from hexanes to give the title compound, mp=81°; NMR (DMSO-d6) δ 7.51, 7.15-7.25, 4.43, 3.81, 3.00-3.26 and 1.49; CMR (DMSO-d6) δ 172.43, 163.74, 161.20, 155.67, 142.58, 112.70, 120.23, 78.69, 54.71, 52.24, 39.25 and 28.37.

Workup

  1. customTo a 1-L 3-neck round bottom flask equipped with a magnetic stirrer, nitrogen inlet
  2. temperaturethe contents are cooled to 0°
  3. temperatureOnce cooled
  4. stirringstirred for 30 min
  5. temperatureThe mixture is then heated to about 50°
  6. temperatureAt that time, the mixture is cooled to below 20° (solids form)
  7. stirringstirred for 15 min
  8. extractionthen extracted with methyl t-butyl ether (200 mL)
  9. customThe phases are separated
  10. extractionthe aqueous layer is extracted with methyl t-butyl ether (2×200 mL)
  11. washThe combined organic phases are washed with water (400 mL)
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated under reduced pressure
  15. customto give a solid
  16. customThis material is then recrystallized from hexanes

Sources & evidence

ORD record
ord-1dcadfed776048b6bd73a519b5f1aecc
Source dataset
uspto-grants-2005_02
Patent number
US06849750B2

Reaction notes

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