4-Methylmorpholine → 6-Fluoro-7-(2-fluoro-4-iodophenylamino)-8-(3-hydroxyazetidine-1-carbonyl)-2,3-dihydroindolizin-5(1H)-one

HRID 910151Notes

Reaction equation

[F:1][C:2]1[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20](O)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.Cl.[OH:25][CH:26]1[CH2:29][NH:28][CH2:27]1.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[C:3](=[O:23])[N:4]2[C:8](=[C:9]([C:20]([N:28]3[CH2:29][CH:26]([OH:25])[CH2:27]3)=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2

Participants

Conditions

Temperature: 75 °C

Procedure

Example 1 (100 mg, 0.23 mmol) was added to a suspension of 3-hydroxyazetidine hydrochloride (50 mg, 0.46 mmol), HATU (132 mg, 0.35 mmol), and N-methylmorpholine (0.13 mL, 1.15 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 5 hours and then concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified via preparative HPLC (25/70 acetonitrile/water) to give 74 mg (76%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.59 (dd, 1H, J=10.6, 1.8 Hz), 7.72 (dd, 1H, J=8.6, 1.7 Hz), 6.88 (t, 1H, J=8.3 Hz), 5.32 (s, 1H), 4.31-4.48 (m, 2H), 4.05-4.15 (m, 1H), 3.98 (t, 2H, J=6.6 Hz), 3.83-3.94 (m, 1H), 3.72 (m, 1H), 3.50 (m, 1H), 2.89-3.06 (m, 2H), 2.06-2.12 (m, 2H). MS (ES) [m+H] calc'd for C18H16F2IN3O3, 488. found 488.

Workup

concentrationconcentrated in vacuo
custommethanol (1.5 mL) and purified via preparative HPLC (25/70 acetonitrile/water)

Sources & evidence

ORD record: ord-35fcdac87ae3445ca96a9885ddc88b80
Source dataset: uspto-grants-2011_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08022057B2

Reaction notes

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