application background and overview of 4-cyanopyridine n-oxide
4-cyanopyridine n-oxide is an intermediate in the preparation of topirastat. the trade name of topirastat is topiloric, its chemical name is: 5-(2-cyano-4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, which is a non-purine the xanthine-like oxidoreductase selective inhibitor was jointly developed by japan’s fuji pharmaceutical co., ltd. and sanwa chemical research institute. a marketing application was submitted to the japanese ministry of health, labor and welfare in june 2012, and was approved on june 28, 2013.
application preparation of 4-cyanopyridine n-oxide
in a 250ml three-necked bottle, add 1g of tungsten powder to 10ml of 30% mass percent hydrogen peroxide. after reacting with sodium carbonate for 20 minutes at 40-50°c, add 100ml of methanol, 20g of 4-cyanopyridine, and 20ml of mass percent. 30% hydrogen peroxide, heat up to 60-65°c, react for 6 hours. after the reaction is completed, cool and crystallize naturally. when the temperature cools to 25°c, continue stirring for 1 hour, filter and dry to obtain 20.5g of white crystals, namely 4-cyano. pyridine n-oxide, yield 89.1%, hplc purity (normalized method): 99.8%. nmr data related to 4-cyanopyridine n-oxide: 1hnmr (mhz, dmso), 7.92 (d, j = 7.2, 2h), 8.39 (d, j = 7.2, 2h)
applications of 4-cyanopyridine n-oxide
the steps for preparing topinostat are as follows:
step 1: add sodium methoxide to 4-cyanopyridine n-oxide for reaction, and then add ammonium chloride biborate pinacol ester to generate intermediate 2;
step 2: in the presence of copper bromide catalyst, sodium carbonate, and dmf solvent, intermediate 2 and 4-cyanopyridine undergo a ring-forming reaction to generate intermediate 3;
step 3: react trimethylsilyl cyanide and intermediate 3 in n,n-dimethylacetamide solution (dmac), and then add n,n-dimethylformyl chloride to react to obtain topirastat .