反应详情

温度

0 °C

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).

1. stirringthe mixture stirred at 0° C. for 30 mins
2. customThe crude mixture was partitioned between saturated aqueous sodium bicarbonate solution (10 ml) and DCM (10 ml)
3. customThe organic layer was separated
4. washwashed with water (10 ml)
5. concentrationconcentrated in vacuo
6. customto give an orange solid which
7. customwas purified by column chromatography (80 g silica RediSep column)
8. washeluting with 0-10% MeOH/DCM over 20 column volumes
9. customSeparation
10. customthe solvent was removed in vacuo
11. customThe resultant orange solid was re-purified by column chromatography on silica (80 g silica RediSep column)
12. washeluting with 50-100% EtOAc/cyclohexane over 40 mins on the ISCO Companion
13. additionFractions containing desired material