Tetrahydrofuran → (S)-(9H-fluoren-9-yl)methyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate

HRID 596040Notes

Reaction equation

HRID 596040 reaction equation
[NH2:1][C@@H:2]([C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([F:12])[CH:6]=1)[CH2:3][OH:4].C1COCC1.C([O-])(O)=O.[Na+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(OCC)(=O)C.O>[F:12][C:7]1[CH:6]=[C:5]([C@H:2]([NH:1][C:23](=[O:39])[O:24][CH2:25][CH:26]2[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:32]3[C:27]2=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:3][OH:4])[CH:10]=[C:9]([I:11])[CH:8]=1

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 343679-Fluorenylmethyl chloroformateHCID 516892Sodium BicarbonateHCID 118045250(S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol

Product 1

HCID 118054608(S)-(9H-fluoren-9-yl)methyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamateYield 75.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

To (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethanol (4500 mg, 14.17 mmol) was added THF (Volume: 40 mL, Ratio: 2.67) and water (Volume: 15 mL, Ratio: 1.000), followed by NaHCO3 (4762 mg, 56.7 mmol). The mixture was stirred for 2 minutes then cooled to 0° C. in an ice bath. To the reaction was added (9H-fluoren-9-yl)methyl carbonochloridate (5499 mg, 21.26 mmol) and the reaction was stirred at 0° C. for 30 minutes, allowed to warm to room temperature and stirred for a further 60 minutes, before conducting LCMS. Ethyl acetate was added to the crude reaction mixture. The mixture was washed with water (2×), saturated salt solution, dried sodium sulfate, filtered and concentrated to residue. The crude product was purified by silica gel chromatography using a 300 g column (solid load) eluting from 0-60% ethyl acetate in heptane. The desired fractions were concentrated to constant mass to give as white solid 5375 mg of the desired product as free base used as is, (73% yield). LCMS (m/z): 504.1 (MH+), 1.05 min. 1H NMR (<cd3od>) d: 7.78 (d, J=7.4 Hz, 2H), 7.64 (d, J=7.2 Hz, 2H), 7.53 (s, 1H), 7.33-7.43 (m, 3H), 7.25-7.33 (m, 2H), 7.07 (d, J=9.2 Hz, 1H), 4.64 (t, J=5.9 Hz, 1H), 4.31-4.46 (m, 2H), 4.21 (t, J=6.3 Hz, 1H), 3.66 (d, J=3.1 Hz, 2H).

Workup

  1. stirringthe reaction was stirred at 0° C. for 30 minutes
  2. temperatureto warm to room temperature
  3. stirringstirred for a further 60 minutes
  4. customreaction mixture
  5. washThe mixture was washed with water (2×), saturated salt solution, dried sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to residue
  8. customThe crude product was purified by silica gel chromatography
  9. washeluting from 0-60% ethyl acetate in heptane
  10. concentrationThe desired fractions were concentrated to constant mass

Sources & evidence

ORD record
ord-f6b261be1b494d899518abd69ce08535
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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