Methyl iodide → 2-(2,5-Dichloro-phenoxy)-5-fluoro-N-(2-methoxy-pyridin-3-yl)-N-methyl-nicotinamide

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Reaction Steps

To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinic acid (100 mg, 0.33 mmol, 1.0 equiv; Example 80, Step 1) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (213 mg, 282 μL, 1.65 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (151 mg, 0.40 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt. After 1 h, 3-amino-2-methoxypyridine (49 mg, 0.40 mmol, 1.2 equiv; [CAS RN 20265-38-7]) was added and stirring at rt continued over night. The reaction mixture was extracted from a sat. solution of NaHCO3 (100 mL) with dichloromethane (3×50 mL), the combined organic phases dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude reaction mixture redissolved in DMF (1.5 mL). To this solution was added sodium hydride (28.6 mg, 0.66 mmol, 2.0 equiv; 55% free-flowing powder moistened with oil; [CAS RN 7646-69-7]) and iodomethane (93.7 mg, 41 μL, 0.66 mmol, 2.0 equiv; [CAS RN 74-88-4]) and the reaction mixture stirred at rt for 30 min. 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 28.5 mg (20%) of the title compound. MS (ISP): 422.0 [M+H]+.

Provenance & Evidence