Diisopropylethylamine → [3,4-Bis(Fluoranyl)-2-[(2-Fluoranyl-4-Iodanyl-Phenyl)amino]phenyl]-(3-Oxidanylazetidin-1-Yl)methanone

HRID 1717531Notes

Reaction equation

HRID 1717531 reaction equation
[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH:55]1[CH2:58][CH:57]([OH:59])[CH2:56]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:55]2[CH2:58][CH:57]([OH:59])[CH2:56]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 27592903-Hydroxyazetidine hydrochlorideHCID 220256632-(2-Fluoro-4-iodoanilino)-3,4-difluorobenzoic acid

Product 1

HCID 16223325[3,4-Bis(Fluoranyl)-2-[(2-Fluoranyl-4-Iodanyl-Phenyl)amino]phenyl]-(3-Oxidanylazetidin-1-Yl)methanoneYield 88%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g, 5.3 mmol) and the mixture was allowed to stir at room temperature over 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stir an additional hour at room temperature. The mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was then washed with water (3×) then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography using ethyl acetate:hexanes (5:1) eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (2.09 g, 87% yield) as a colorless amorphous solid. 1H NMR (400 MHz, CDCl3): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m, 2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).

Workup

  1. stirringto stir an additional hour at room temperature
  2. customThe mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution
  3. washThe organic layer was then washed with water (3×)
  4. dry with materialbrine and dried over anhydrous sodium sulfate
  5. filtrationFiltration and concentration

Sources & evidence

ORD record
ord-dc081480e5764419952ae836d6764ed7
Source dataset
uspto-grants-2010_09
Patent number
US07803839B2

Reaction notes

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