Methyl iodide → N-(2,6-Dichloro-3-methoxy-phenyl)-2-(2,5-dichloro-phenoxy)-5-fluoro-N-methyl-nicotinamide

HRID 1877408Notes

Reaction equation

HRID 1877408 reaction equation
[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][C:5]1[N:13]=[CH:12][C:11]([F:14])=[CH:10][C:6]=1[C:7](Cl)=[O:8].[CH2:20](N(C(C)C)C(C)C)C.[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[NH2:39].[H-].[Na+].IC>CN(C=O)C>[Cl:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[N:39]([CH3:20])[C:7](=[O:8])[C:6]1[CH:10]=[C:11]([F:14])[CH:12]=[N:13][C:5]=1[O:4][C:3]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:2]=1[Cl:1]

Participants

7

Reactant 5

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 81531DiisopropylethylamineHCID 205138882,6-Dichloro-3-methoxyanilineHCID 866412572-(2,5-Dichloro-phenoxy)-5-fluoro-nicotinoyl chloride

Product 1

HCID 59294505N-(2,6-Dichloro-3-methoxy-phenyl)-2-(2,5-dichloro-phenoxy)-5-fluoro-N-methyl-nicotinamideYield 7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinoyl chloride (76.6 mg, 0.24 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (155 mg, 205 μL, 1.2 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 2,6-dichloro-3-methoxy-phenylamine (50.7 mg, 0.264 mmol, 1.1 equiv; [CAS RN 55285-43-3]) and the reaction mixture stirred at rt over night. To this solution was added sodium hydride (20.6 mg, 0.48 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and iodomethane (68.2 mg, 29 μL, 0.48 mmol, 2.0 equiv; [CAS RN 74-88-4]) and stirring of the reaction mixture at rt continued for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 8.1 mg (7%) of the title compound as an off-white powder. MS (ISP): 490.9 [M+H]+.

Workup

  1. stirringstirring of the reaction mixture at rt
  2. customRemoval of the solvent mixture
  3. customunder reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  4. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  5. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-45d0341fd3dc4886b075fc16c966615e
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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