Pyridine → 6-(Chloromethyl)-N-[6-{6-chloro-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-2-pyridinecarboxamide

Participants

Reaction Conditions

Reaction Steps

To a solution of 6-(hydroxymethyl)-2-pyridinecarboxylic acid (500 mg, 3.27 mmol) in chloroform (10 ml) and DMF (0.1 ml) was added thionyl chloride (1 ml, 13.70 mmol) and the mixture heated at 65° C. for 1 hr. Solvent was removed in vacuo and the residue was azeotroped with chloroform (5 ml) then dried on a high vacuum line for 30 mins to afford an orange oil (650 mg), presumed to be 6-(chloromethyl)-2-pyridinecarbonyl chloride. N-{5-[4-amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-chloro-3-pyridinyl}methanesulphonamide (600 mg, 1.255 mmol) was dissolved in DCM (5 ml) and pyridine (0.122 mL, 1.506 mmol) was added followed by 6-(chloromethyl)-2-pyridinecarbonyl chloride (281 mg, 1.255 mmol) in DCM (5 ml). The reaction was stirred at 0° C. for 1 hr. A further portion of 6-(chloromethyl)-2-pyridinecarbonyl chloride (281 mg, 1.255 mmol) was added and the mixture stirred at 0° C. for 30 mins. The crude mixture was partitioned between saturated aqueous sodium bicarbonate solution (10 ml) and DCM (10 ml). The organic layer was separated using a hydrophobic frit, washed with water (10 ml) and concentrated in vacuo to give an orange solid which was purified by column chromatography (80 g silica RediSep column) eluting with 0-10% MeOH/DCM over 20 column volumes. Separation was incomplete, so all fractions were combined and the solvent was removed in vacuo. The resultant orange solid was re-purified by column chromatography on silica (80 g silica RediSep column) eluting with 50-100% EtOAc/cyclohexane over 40 mins on the ISCO Companion. Fractions containing desired material were combined to afford the title compound as a pale yellow solid (141 mg).

Provenance & Evidence