Synthesis And Polymorphic Behavior Investigation Of Potential Non-Steroidal Anti-Inflammatory Drugs

Non-steroidal anti-inflammatory drugs(NSAIDs),the world's largest prescription drugs,have the advantage of having no adversary effects such as addiction and dependency and so on,but it may cause gastrointestinal toxicity.At present,improving bioavailability and reducing toxicity is a hot topic for safer NSAIDs,and the bioavailability and pharmacodynamics are closely related to the crystal form of the drugs.Thus,we set out to look for better NSAIDs and also study the polymorphism of the compounds.Based on the previous research of our lab,we have carried out structural modification of Clonixin by designing two series of compounds,one with bulky groups attached to the nitrogen bridging the two aromatic rings,the other with flourine(s)on the benzene ring and methyl on the nitrogen bridging the two aromatic rings.This designation helps us to study the polymorphism of potential drugs and the effect of substituents on the intermolecular interactions.Firstly,six compounds were synthesized by reacting 2-chloronicotinic acid with phenylamine analogs with p-TsOH as catalyst under a nucleophilic aromatic substitution(SNAr)mechanism according to literature,and confirmed by NMR,FTIR and MS.Different crystal forms were obtained in a variety of solvents by slow evaporation.The structures of the different crystal polymorphs were solved by single-crystal X-ray diffraction,and some compounds showed the behavior of polymorphism.According to the crystal packing,the carboxylic acid-pyridine heterosynthon was observed in all the crystals except for one form of one of the compounds which had the unique co-existence of both acid-acid homosynthon and acid-pyridine heterosynthon.And the molecules take a twisted conformation,which also can be confirmed by UV-Vis,dihedral angle measurement and superposition of the molecules of the polymorphs.In summary,most of the compounds tested in this paper showed the behavior of polymorphism,and a new strategy was applied to produce 2-anilinonicotinic acid crystals with exclusive carboxylic acid-pyridine heterosynthon.How molecular conformation can affect intermolecular interactions and consequent crystal packing was also discussed.