4-Methylmorpholine → HCID 86621260, compound

HRID 1808957Notes

Reaction equation

HRID 1808957 reaction equation
[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:61]1[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])[CH2:62]1>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:61]2[CH2:64][CH:63]([NH:65][C:66](=[O:72])[O:67][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:62]2)=[O:8])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])[CH:3]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 15194053-Aminoazetidine, 3-BOC protectedHCID 2724699PyBOPHCID 22286045HCID 22286045, compound

Product 1

HCID 86621260HCID 86621260, compoundYield 95.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (100 mg, 0.25 mmol) was taken into DMF (1 mL) followed by addition of PyBOP (137 mg, 0.26 mmol) and the mixture was stirred for 15 minutes then NMM (60 μL, 0.5 mmol) and commercially available 1,1-dimethylethyl azetidin-3-ylcarbamate (43 mg, 0.25 mmol) were subsequently added. The mixture was allowed to stir for 12 hours at room temperature then partitioned with ethyl acetate and water. The organic phase was washed three times with additional water then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography of the residue using hexanes:ethyl acetate 3:1 as eluent afforded 1,1-dimethylethyl [1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-yl]carbamate (131 mg) as a colorless oil. The oil was taken into trifluoroacetic acid (1 mL) and allowed to stand at room temperature for 5 minutes then concentrated in vacuo. The residue was portioned with ethyl acetate and saturated aqueous sodium bicarbonate and the organic phase washed with brine then dried over anhydrous sodium sulfate. The organic solution was filtered and concentrated then the residue taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane until the solution was acidic. The solution was concentrated and the residue triturated with ethyl ether to give a thick precipitate. The solid was collected by filtration and dried in vacuo to give 1-({4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-amine hydrochloride (67 mg, 55% overall yield). 1H-NMR (400 MHz, D6-DMSO): 9.02 (s, 1H), 8.54 (br s, 3H), 7.68 (dd, 1H), 7.53-7.47 (m, 2H), 7.22 (tr, 1H), 7.16 (dd, 1H), 4.60 (br s, 1H), 4.23 (br s, 2H), 4.03 (br m, 2H). MS (EI) for C16H13F3IN3O: 448 (MH+).

Workup

  1. stirringto stir for 12 hours at room temperature
  2. customthen partitioned with ethyl acetate and water
  3. washThe organic phase was washed three times with additional water
  4. dry with materialbrine and dried over anhydrous sodium sulfate
  5. filtrationFiltration and concentration

Sources & evidence

ORD record
ord-a5789ff249eb4c909a9c03350222104f
Source dataset
uspto-grants-2013_01
Patent number
US08362002B2

Reaction notes

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