Methyl iodide → (1R,3S,5R)-3-[(S)-1-(3-Chloro-2-fluoro-phenyl)-2-methoxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

HRID 1527368Notes

Reaction equation

HRID 1527368 reaction equation
[H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@H:15]([C:16](=[O:29])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][OH:20])[CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:9])([CH3:6])([CH3:5])[CH3:4].IC.[C:32]([O-])(O)=O.[Na+]>C1COCC1.C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[C@H:15]([C:16](=[O:29])[NH:17][C@@H:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[CH2:19][O:20][CH3:32])[CH2:14][C@@H:13]2[C@H:11]1[CH2:12]2)=[O:9])([CH3:6])([CH3:4])[CH3:5]

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 68283751(1R,3S,5R)-3-[(S)-1-(3-Chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

Product 1

HCID 68284464(1R,3S,5R)-3-[(S)-1-(3-Chloro-2-fluoro-phenyl)-2-methoxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of NaH (60% in mineral oil, 25.7 mg, 0.64 mmol) in THF (3 mL) cooled at 0° C. under Argon was added (1R,3S,5R)-3-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (270 mg, 0.64 mmol). The reaction mixture was stirred at 0° C. for 30 min and iodomethane (0.06 mL, 0.97 mmol) was added. After 1 h the reaction mixture was poured into saturated NaHCO3 aqueous solution. CH2Cl2 was added, the layers were separated and the aqueous one back-extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 20:80) the desired compound as a colorless oil. TLC, Rf (EtOAc)=0.65; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.4/459.4 [M+HCOO]−; tR (HPLC conditions a): 3.67 min.

Workup

  1. customthe layers were separated
  2. extractionthe aqueous one back-extracted with CH2Cl2 (×3)
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude material was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 20:80) the desired compound as a colorless oil
  7. custom3.67 min.

Sources & evidence

ORD record
ord-4b4612c8c39748d6814d0c939f5f9ec5
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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