Methyl iodide → 2-(2,5-Dichloro-phenoxy)-N-(2-ethyl-phenyl)-N-methyl-nicotinamide

HRID 1877358Notes

Reaction equation

HRID 1877358 reaction equation
[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27])[CH3:20].[CH2:28](N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[H-].[Na+].IC>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:19][CH3:20])[CH3:28])=[O:9]

Participants

9

Reactant 6

HCID 6328Methyl iodideHCID 8471TriethylamineHCID 113572-EthylanilineHCID 24758Sodium hydrideHCID 1670692-Chloro-1-methylpyridinium iodideHCID 167959962-(2,5-Dichloro-phenoxy)-nicotinic acid

Product 1

HCID 461951252-(2,5-Dichloro-phenoxy)-N-(2-ethyl-phenyl)-N-methyl-nicotinamideYield 8.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (59.7 mg, 0.21 mmol, 1.0 equiv; Example 31, Step 1) in dichloromethane (2.0 mL) was added 2-ethyl-phenylamine (27.9 mg, 0.23 mmol, 1.1 equiv; [CAS RN 578-54-1]), triethylamine (42.5 mg, 59 μL, 0.42 mmol, 2.0 equiv; [CAS RN 121-44-8]) and 2-chloro-1-methylpyridinium iodide (59.0 mg, 0.23 mmol, 1.1 equiv; [CAS RN 14338-32-0]) and the reaction mixture stirred at 40° C. over night. The solvent was removed by evaporation under reduced pressure and the crude reaction mixture redissolved in DMF (1 mL). To this solution was added sodium hydride (13.8 mg, 0.32 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and iodomethane (59.6 mg, 26 μL, 0.42 mmol, 2.0 equiv; [CAS RN 74-88-4]) and the reaction mixture stirred at 35° C. for 1 h. 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 6.9 mg (8%) of the title compound. MS (ISP): 401.2 [M+H]+.

Workup

  1. customThe solvent was removed by evaporation under reduced pressure
  2. customthe crude reaction mixture
  3. stirringthe reaction mixture stirred at 35° C. for 1 h
  4. customPurification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column
  5. customequipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps
  6. washa Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Sources & evidence

ORD record
ord-c7f95de0f87f47b8bdb78b1ea5811c2b
Source dataset
uspto-grants-2012_11
Patent number
US08309734B2

Reaction notes

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