The nitration of pyridine, quinoline and isoquinoline derivatives are usually very difficult even under the most vigorous conditions. The yields one usually obtains are also very low. Pyridine itself is about a million times less reactive than benzene. The pyridinium cation (the major species under traditional electrophilic substitution conditions) is about 10-20 times less reactive than benzene.
Recently we had a need to make a nitro substituted isoquinoline derivative as an advanced pharmaceutical intermediate with the nitro group in the 7-position, and do this at the 50 kg-100 kg scale. In addition, the purity specifications were very stringent in that the impurities had to meet ICH guidelines and thus all the impurities needed to be below 0.1 %. All the classical nitration techniques using nitric acid and various solvents gave very poor yields and resulted in the formation of different decomposition products. For example performing the nitration in acetic anhydride gave us a by a product from the acetylation of the starting material. Carrying out the nitration in acetic acid or trifluoroacetic acid provided less decomposition but the conversion was still very low. After extensive experimentation with several different reagents and solvents, we found that the reaction works the best when nitronium tetrafluoroborate is used in a non-protic solvent. The assay and purity of the nitronium tetrafluoroborate was also critically important for this reaction. Ultimately we successfully scaled this chemistry to the pilot plant and were able to make an 80 kg batch of an important pharmaceutical intermediate to support one of our NCE programs. You only have a problem when you can’t find a solution!