m-Chloroperbenzoic acid → 3-(5-Chloro-3-fluoro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

HRID 237278Notes

Reaction equation

HRID 237278 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:14]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:14]=2[OH:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 70297m-Chloroperbenzoic acid2×HCID 23665763Sodium BisulfiteHCID 873651953-(5-Chloro-3-fluoro-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 673500643-(5-Chloro-3-fluoro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl esterYield 46%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of the title compound of Step B (650 mg, 2.0 mmol) in CH2Cl2 (100 mL) was added 77% m-CPBA (510 mg, 3.0 mmol). After stirring for 72 h, the starting aldehyde remained as determined by analytical HPLC analysis. Thus an additional portion of m-CPBA (790 mg, 4.6 mmol) was added. After 18 h, analytical HPLC analysis indicated that the reaction was complete. A solution of 10% aqueous sodium bisulfite (100 mL) was added to the reaction mixture. After an additional 18 h, CH2Cl2 was added and the aqueous portion extracted three times with CH2Cl2. The combined organic extracts were washed with saturated NaHCO3 (2×) and concentrated. The residue was then treated with MeOH (500 mL) and 1 N NaOH (250 mL). The solution immediately turned dark brown. After 2 h, the MeOH was removed by rotary evaporation and 1 M KHSO4 was added to the residue until the pH of the solution reached pH=4. The reaction mixture was then extracted with EtOAc (3×). The combined organic layers were washed with brine and dried. The residue was purified by RP HPLC to provide the desired phenol (290 mg, 46%). 1H NMR (CDCl3): 6.74 (dd, J=10.1, 2.3 Hz, 1H), 6.30 (dd, J=2.0, 2.1 Hz, 1H), 4.87-4.80 (m, 1H), 4.26 (dd, J=9.9, 6.4 Hz, 2H), 4.00 (dd, J=9.9, 3.8 Hz, 2H), 3.29-3.13 (m, 1H), 1.40 (s, 9H).

Workup

  1. waitAfter 18 h
  2. waitAfter an additional 18 h
  3. extractionthe aqueous portion extracted three times with CH2Cl2
  4. washThe combined organic extracts were washed with saturated NaHCO3 (2×)
  5. concentrationconcentrated
  6. additionThe residue was then treated with MeOH (500 mL) and 1 N NaOH (250 mL)
  7. waitAfter 2 h
  8. customthe MeOH was removed by rotary evaporation and 1 M KHSO4
  9. additionwas added to the residue until the pH of the solution
  10. extractionThe reaction mixture was then extracted with EtOAc (3×)
  11. washThe combined organic layers were washed with brine
  12. customdried
  13. customThe residue was purified by RP HPLC

Sources & evidence

ORD record
ord-0969edfa09c04b47ad38e36765ea73de
Source dataset
uspto-grants-2014_02
Patent number
US08642583B2

Reaction notes

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