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

HRID 910160ノート

反応式

HRID 910160 の反応式
[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]

参加物

6

反応物 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

生成物 1

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

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

反応条件

温度
75 °C

実験手順

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.

後処理

  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)

出典と根拠

ORDレコード
ord-2240f7e864de4fd1a7d77c78619b228c
出典データセット
uspto-grants-2011_09
特許番号
US08022057B2

反応ノート

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