Ethyl N-methoxy-N-methylcarbamate → 3-(5-Fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-8-carboxylic acid methoxy-methyl-amide

HRID 226115Notes

Reaction equation

HRID 226115 reaction equation
[F:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]4=[N:12][C:11]=3[CH3:20])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:23][O:24][N:25]([CH3:31])[C:26](=O)[O:27]CC.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:23][O:24][N:25]([CH3:31])[C:26]([C:18]1[C:13]2[N:14]([C:10]([C:7]3[S:6][C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=4[C:8]=3[CH3:9])=[C:11]([CH3:20])[N:12]=2)[N:15]=[C:16]([CH3:19])[CH:17]=1)=[O:27]

Participants

5

Reactant 3

HCID 533715Ethyl N-methoxy-N-methylcarbamateHCID 2724682Lithium diisopropylamideHCID 688598503-(5-Fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine

Product 1

HCID 866210453-(5-Fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-8-carboxylic acid methoxy-methyl-amideYield 31.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

The solution of 3-(5-fluoro-3-methyl-benzo[b]thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (2.09 g, 6.73 mmol) in THF (56 mL) is stirred at −78° C. Ethyl N-methoxy-N-methylcarbamate (4.48 g, 33.7 mmol) is added. LDA (10 mL, 20.1 mmol) is added dropwise to maintain reaction temperature at −75° C. The reaction is stirred at −78° C. for 1 hour. The mixture is quenched with H2O, filtered through celite with CH2Cl2. The collect solution is washed with H2O, dried over Na2SO4, filtered and concentrated. The crude is purified by ISCO (50-100% EtOAc/Hexane) to give the title compound (0.85 g, 31%). 1H NMR (CDCl3): δ 7.8 (dd, J=4.8, 8.5 Hz, 1H), 7.5 (dd, J=2.5, 9.7 Hz, 1H), 7.2 (m, 1H), 7.0 (s, 1H), 3.7 (s, 3H), 3.5 (s, 3H), 2.6 (s, 3H), 2.55 (s, 3H), 2.3 (s, 3H) ppm. MS (m/e): 399 (100%, M+1).

Workup

  1. temperatureto maintain
  2. customreaction temperature at −75° C
  3. customThe mixture is quenched with H2O
  4. filtrationfiltered through celite with CH2Cl2
  5. washThe collect solution is washed with H2O
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude is purified by ISCO (50-100% EtOAc/Hexane)

Sources & evidence

ORD record
ord-8fc792b35b1541978efcda4e44742859
Source dataset
uspto-grants-2009_07
Patent number
US07557103B2

Reaction notes

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