Triethylamine → 7-(4-Ethynyl-2-fluorophenylamino)-6-fluoro-N-(2-hydroxyethoxy)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide

HRID 910163Notes

Reaction equation

HRID 910163 reaction equation
[F:1][C:2]1[C:3](=[O:27])[N:4]2[C:8](=[C:9]([C:20]([NH:22][O:23][CH2:24][CH2:25][OH:26])=[O:21])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:13]=1[F:19])[CH2:7][CH2:6][CH2:5]2.[Si]([C:32]#[CH:33])(C)(C)C.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CN(C=O)C>[C:32]([C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[C:9]([C:20]([NH:22][O:23][CH2:24][CH2:25][OH:26])=[O:21])=[C:8]3[N:4]([CH2:5][CH2:6][CH2:7]3)[C:3](=[O:27])[C:2]=2[F:1])=[C:13]([F:19])[CH:14]=1)#[CH:33]

Participants

9

Reactant 4

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 66111TrimethylsilylacetyleneHCID 426062046-Fluoro-7-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamide

Product 1

HCID 426063207-(4-Ethynyl-2-fluorophenylamino)-6-fluoro-N-(2-hydroxyethoxy)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxamideYield 60.4%

Reagents, catalysts & solvents 4

HCID 83717Copper iodideCatalystHCID 178418476HCID 178418476, compoundCatalystHCID 21899815MeOH tetrahydrofuranSolventHCID 21974620tetrahydrofuran N,N-dimethylformamideSolvent

Procedure

Example 4 (25 mg, 0.051 mmol), TMS-acetylene (6 mg, 0.051 mmol), copper iodide (1 mg, 0.0005 mmol), triethylamine (1.0 mL, 0.014 mmol), and dichlorobis(triphenylphosphine)palladium(II) (1 mg, 0.0005 mmol) were stirred in 1:1 THF/DMF (2 mL) at room temperature for 3 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10% MeOH/CH2Cl2) to give a tan oil. The intermediate was dissolved in 1:1 THF/MeOH (2 mL) and solid potassium carbonate (14 mg, 0.10 mmol) was added and the mixture stirred for 1 hr. The potassium carbonate was filtered off and the solution was concentrated in vacuo and purified by prep HPLC (25/50, water/acetonitrile) to give 12 mg (60%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4): δ 7.15-7.27 (m, 2H), 7.00 (t, 1H, J=8.3 Hz), 4.16 (t, 1H, J=7.3 Hz), 3.83-3.84 (m, 2H), 3.68-3.69 (m, 2H), 3.51 (s, 1H), 3.27 (t, 2H, J=7.6 Hz), 2.28 (s, 1H), 2.24 (m, 2H). MS (ES) [m+H] calc'd for C19H17F2N3O4, 390. found 390.

Workup

  1. concentrationThe solution was concentrated in vacuo
  2. custompurified by silica gel chromatography (10% MeOH/CH2Cl2)
  3. customto give a tan oil
  4. additionwas added
  5. filtrationThe potassium carbonate was filtered off
  6. concentrationthe solution was concentrated in vacuo
  7. custompurified by prep HPLC (25/50, water/acetonitrile)

Sources & evidence

ORD record
ord-97631e93fe394f47b7a6998db4a610be
Source dataset
uspto-grants-2011_09
Patent number
US08022057B2

Reaction notes

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