Applications of 4-cyanopyridine N-oxide_Industrial additives

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 .