Water → HCID 59469004, compound

HRID 1808983Notes

Reaction equation

HRID 1808983 reaction equation
[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH:16]([N+:20]([O-])=O)[CH:17]([CH3:19])[CH3:18])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Fe]>[NH2:20][CH:16]([C:13]1([OH:15])[CH2:12][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[O:10])[CH2:14]1)[CH:17]([CH3:18])[CH3:19]

Participants

7

Reactant 4

HCID 962WaterHCID 8028TetrahydrofuranHCID 2723923Ammonium formate2×HCID 67051798HCID 67051798, compound

Product 1

HCID 59469004HCID 59469004, compoundYield 20.7%

Reagents, catalysts & solvents 2

HCID 23925IronCatalyst2×HCID 8857Ethyl AcetateSolvent

Procedure

1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-(2-methyl-1-nitropropyl)azetidin-3-ol (189 mg, 0.34 mmol) was taken into 4:1 THF:water (5 mL) followed by addition of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) and the mixture was heated to reflux. After four hours additional aliquots of iron powder (192 mg, 3.4 mmol) and ammonium formate (429 mg, 6.8 mmol) were added and the mixture was allowed to reflux an additional 12 hours. The mixture was cooled to room temperature and diluted with ethyl acetate then filtered. The filtrate was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate then the organic layer washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a residue that was further purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents to give a residue (36.5 mg) that was further purified by preparative reverse phase HPLC to give 3-(1-amino-2-methylpropyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol trifluoroacetate salt (7.9 mg) as a colorless amorphous solid after lyophilization of the combined pure fractions. 1H-NMR (400 MHz, D6-DMSO): 8.63 (s, 1H), 7.58 (dd, 1H), 7.37 (d, 1H), 7.35-7.31 (m, 1H), 7.17 (q, 1H), 6.71-6.66 (m, 1H), 4.23 (dd, 1H), 4.03 (dd, 1H), 3.80 (dd, 1H), 3.66 (dd, 1H), 2.34 (dd, 1H), 1.79-1.70 (m, 1H), 0.84-0.77 (m, 6H). MS (EI) for C20H21F3IN3O2: 520 (MH+).

Workup

  1. temperaturethe mixture was heated to reflux
  2. temperatureto reflux an additional 12 hours
  3. filtrationthen filtered
  4. customThe filtrate was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate
  5. washthe organic layer washed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationFiltration and concentration
  8. customafforded a residue that
  9. customwas further purified by silica gel flash chromatography

Sources & evidence

ORD record
ord-e55327f9673445eeab9a9c4bcdbb8197
Source dataset
uspto-grants-2013_01
Patent number
US08362002B2

Reaction notes

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