4-Methylmorpholine → 7-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-6-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide

HRID 910160Notes

Reaction equation

HRID 910160 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23].C([O:28][CH2:29][CH2:30][O:31][NH2:32])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([NH:32][O:31][CH2:30][CH2:29][OH:28])=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 46856370O-(2-tert-butoxyethyl)hydroxylamineHCID 576898057-(2-Fluoro-4-iodophenylamino)-6-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylic acid

Product 1

HCID 426063177-(2-Fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-6-methyl-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamideYield 5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
75 °C

Procedure

Compound 8e (76 mg, 0.23 mmol) was added to a suspension of O-(2-tert-butoxy-ethyl)-hydroxylamine (see, WO05/110410, 47 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), and N-methylmorpholine (0.10 mL, 0.90 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 16 h and concentrated in vacuo. The resulting oil was dissolved in 3 mL of TFA and allowed to stir at RT for 2 h. Then MeOH (3 mL) was added and made basic with potassium carbonate. It was allowed to stir for 30 minutes, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile) to give 4 mg (5%) of Example 8 as a white solid. 1H NMR (400 MHz, MeOD): δ 7.43 (d, 1H, J=8.9 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.43 (t, 1H, J=8.6 Hz), 4.14 (t, 2H, J=7.3 Hz), 3.85 (m, 2H), 3.67 (m, 2H), 3.29 (t. 2H, J=7.6 Hz), 2.09-2.27 (m, 2H), 1.83 (s, 3H). MS (ES) [m+H] calc'd for C18H19FIN3O4, 488. found 488.

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe resulting oil was dissolved in 3 mL of TFA
  3. additionThen MeOH (3 mL) was added
  4. stirringto stir for 30 minutes
  5. filtrationthe solid was filtered off
  6. concentrationthe filtrate was concentrated in vacuo
  7. custommethanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile)

Sources & evidence

ORD record
ord-2240f7e864de4fd1a7d77c78619b228c
Source dataset
uspto-grants-2011_09
Patent number
US08022057B2

Reaction notes

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