Triethylamine → 7-Fluoro-8-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxamide

HRID 910156Notes

Reaction equation

HRID 910156 reaction equation
[F:1][C:2]1[C:3](=[O:24])[N:4]2[C:9](=[C:10]([C:21]([OH:23])=O)[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])[CH2:8][CH2:7][CH2:6][CH2:5]2.C([O:29][CH2:30][CH2:31][O:32][NH2:33])(C)(C)C.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3](=[O:24])[N:4]2[C:9](=[C:10]([C:21]([NH:33][O:32][CH2:31][CH2:30][OH:29])=[O:23])[C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])[CH2:8][CH2:7][CH2:6][CH2:5]2

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 46856370O-(2-tert-butoxyethyl)hydroxylamineHCID 576898117-Fluoro-8-(2-fluoro-4-iodophenylamino)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid

Product 1

HCID 426063167-Fluoro-8-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxamideYield 24%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

7-Fluoro-8-(2-fluoro-4-iodophenylamino)-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylic acid (7e, 216 mg, 0.48 mmol, 1 eq), O-(2-tert-butoxyethyl)hydroxylamine (129 mg, 0.97 mmol, 2 eq) and N-hydroxybenzotriazole (82 mg, 0.53 mmol, 1.1 eq) were stirred in DCM (12 ml) and DMF (1.5 ml). 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide (111 mg, 0.58 mmol, 1.2 eq) and triethylamine (101 μl, 0.73 mmol, 1.5 eq) were added and the solution stirred at RT for 16 hours. After washing with 0.1N HCl (30 ml) then brine (30 ml) the organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was dissolved in TFA and stirred for 2 hours then the solvent was removed in vacuo. The residue was purified by HPLC to give the title compound as a white solid (58 mg, 24%). 1H NMR (400 MHz, MeOD) δ ppm 1.75-1.90 (m, 2H) 1.90-2.01 (m, 2H) 2.76-2.90 (m, 2H) 3.14 (d, J=3.28 Hz, 2H) 3.49 (d, J=3.28 Hz, 1H) 3.68-3.77 (m, 1H) 3.89 (t, J=4.29 Hz, 2H) 3.99-4.10 (m, 2H) 5.50 (s, 1H) 6.83-6.95 (m, 1H) 7.39-7.52 (m, 2H) [M+H] calc'd for C18H18F2IN3O4, 506. found, 506.

Workup

  1. washAfter washing with 0.1N HCl (30 ml)
  2. dry with materialbrine (30 ml) the organic layer was dried over magnesium sulfate
  3. customevaporated to dryness
  4. dissolutionThe residue was dissolved in TFA
  5. stirringstirred for 2 hours
  6. customthe solvent was removed in vacuo
  7. customThe residue was purified by HPLC

Sources & evidence

ORD record
ord-ffe976b2fb3745ee8a5e0b299e08f4ca
Source dataset
uspto-grants-2011_09
Patent number
US08022057B2

Reaction notes

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